Pompe disease GAA variant database

Variant database

Page 1 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
GAA and part of CCDC40 Ch37/hg19:g.78,056,048_ 78,094,854delins14bp r.(-212_*551del) p.(0) Deletion Deletion Deletion (whole gene) Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - deletion of whole GAA gene deletion of whole GAA gene protein is not expressed
CCDC40 and GAA exon 1 Ch37/hg19 chr17:78,059,821_ 78,076,592del r.0 p.? deletion Deletion (intron variant) No category very severe Pathogenic Classic infantile Unknown MAF not reported no effect on splicing no expression found in allele specific PCR protein is not expressed
exon 1A, 5' UTR c.-338C>G r.(-338c>g) p.? Substitution Substitution No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs144639114 no effect on splicing protein is expressed
exon 1A, 5' UTR c.-260G>C r.(-260g>c) p.? Substitution Substitution No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304849 no effect on splicing protein is expressed
exon 1A, 5' UTR c.-178G>A r.(-178g>a) p.? Substitution Substitution No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs77514632 no effect on splicing protein is expressed
intron 1A c.-113+2T>C r.spl p.? substitution substitution/ splicing (splice donor site) No category Very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported affects splicing on exon 1 in minigene loss of exon 1A splice donor site unknown
exon 1B, 5' UTR c.-82G>C r.(-82g>c) p.? Substitution Substitution No category Unknown Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 1B, 5' UTR c.-75C>G r.(-75c>g) p.? Substitution Substitution No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs80020206 no effect on splicing protein is expressed
intron 1B c.-33+219G>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889961 no effect on splicing protein is expressed
intron 1B c.-33+316C>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs8077055 no effect on splicing protein is expressed
intron 1B c.-33+317C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs8077056 no effect on splicing protein is expressed
intron 1B c.-33+671A>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs55751636 no effect on splicing protein is expressed
intron 1B c.-33+757G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs28413147 no effect on splicing protein is expressed
intron 1B c.-33+903A>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12450199 no effect on splicing protein is expressed
intron 1B c.-33+1104A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs11150841 no effect on splicing protein is expressed
intron 1B c.-33+1172G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs1442315 no effect on splicing protein is expressed
intron 1B c.-33+1190G>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12602593 no effect on splicing protein is expressed
intron 1B c.-33+1309T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs1442314 no effect on splicing protein is expressed
intron 1B c.-32-1298G>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12602610 no effect on splicing protein is expressed
intron 1B c.-32-1124C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs58959690 no effect on splicing protein is expressed
intron 1B c.-32-884T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs145362066 no effect on splicing protein is expressed
intron 1B c.-32-793C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs55666739 no effect on splicing protein is expressed
intron 1B c.-32-721G>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs75754966 generates a new cryptic splice accepter site unknown
intron 1B c.-32-686A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs147264695 no effect on splicing protein is expressed
intron 1B c.-32-640C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12600845 no effect on splicing protein is expressed
intron 1B c.-32-521G>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs115060925 generates a new cyptic splice donor site unknown
intron 1B c.-32-494C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs140325572 no effect on splicing protein is expressed
intron 1B c.-32-462G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs74003606 no effect on splicing protein is expressed
intron 1B c.-32-17_-32-10delins(30) r.? p.? Deletion/ insertion deletion/ insertion (intron variant) No category very severe Unknown significance Classic infantile Unknown MAF not reported N.D. unknown
intron 1B c.-32-13T>G r.[=,-32_546del,-32_486del] p.[=,0] Substitution Substitution/ Splicing (intron variant) Deletion (translation initiation site) Potentially mild Pathogenic Childhood or Adult Positive MAF is less than 1% rs386834236 causes partial and complete skipping of exon 2 no effect on splicing detection of leaky wildtype splicing protein is expressed
intron 1B c.-32-3C>G r.(=) p.? Substitution Substitution/ Splicing (intron variant) No category Less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported weakens exon 2 splice acceptor unknown
intron 1B c.-32-3C>A r.(=) p.? Substitution Substitution/ Splicing (intron variant) No category Less severe Pathogenic Childhood Unknown MAF not reported weakens exon 2 splice acceptor unknown
intron 1B c.-32-2A>G r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Childhood or Adult Unknown MAF not reported loss of exon 2 splice acceptor unknown
intron 1B c.-32-1G>C r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 2 splice acceptor and generation of a cryptic splice acceptor site unknown
exon 2 c.1A>T r.(1a>u) p.(0) Substitution Substitution Substitution (translation initiation codon) Potentially less severe Pathogenic Unknown Negative MAF not reported gives 0% residual activity in expression study no effect on splicing - disrupts translation start codon protein is not expressed
exon 2 c.1A>G r.(1a>g) p.(0) Substitution Substitution Substitution (translation initiation codon) Very severe Pathogenic Classic infantile or Childhood Negative MAF not reported no protein on western blot no effect on splicing - disrupts translation start codon no endogeneous protein on western blot protein is not expressed
exon 2 c.2T>C r.(2u>c) p.(0) Substitution Substitution Substitution (translation initiation codon) Potentially less severe Likely pathogenic Childhood Negative MAF not reported gives 0% residual activity in expression study no effect on splicing - disrupts translation start codon protein is not expressed
exon 2 c.3G>A r.(3g>a) p.(0) Substitution Substitution Substitution (translation initiation codon) Very severe Pathogenic Classic infantile or Childhood Negative MAF not reported new cryptic splice acceptor - disrupts translation start codon protein is not expressed
exon 2 c.18_25del r.(18_25del) p.(Cys8Profs*24) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.25del r.(25del) p.(Ser9Profs*34) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 2 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 2 c.40_47del r.(40_47del) p.(Ala14Argfs*18) deletion deletion Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.32G>A r.(32g>a) p.(Arg11Gln) Substitution Substitution Substitution (missense) Non-pathogenic Likely benign Unknown Positive MAF is less than 1% gives 115% residual activity in expression study new cryptic splice acceptor protein is expressed Class C0 (GV: 353.86 - GD: 0.00) Tolerated (score: 0.65) Polymorphism (p-value: 1)
exon 2 c.54C>T r.(54c>u) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 2 c.104T>C r.(104u>c) p.(Phe35Ser) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 353.86 - GD: 0.00) Tolerated (score: 0.17) Polymorphism (prob: 1)
exon 2 c.118C>T r.(118c>u) p.(Arg40*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs767409395 no effect on splicing protein is not expressed
exon 2 c.136T>C r.(136u>c) p.(Ser46Pro) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Classic infantile Positive MAF is less than 1% rs777215354 gives 100% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 353.86 - GD: 0.00) Tolerated (score: 0.26) Polymorphism (p-value: 1)
exon 2 c.147_859-12del r.spl p.? Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 2 c.169C>T r.(169c>u) p.(Gln57*) substitution substitution Substitution (nonsense) very severe Pathogenic Classic infantile Negative MAF not reported rs1057516251 no effect on splicing protein is not expressed
exon 2 c.172C>T r.(172c>u) p.(Gln58*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs201185475 new cryptic splice donor protein is not expressed
exon 2 c.186_196dup r.(186_196dup) p.(Arg66Hisfs*80) Duplication Duplication Frameshift Very severe Uncertain significance Unknown Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.205C>T r.(205c>u) p.(Gln69*) substitution substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs370174315 no effect on splicing protein is not expressed
exon 2 c.199G>A r.(199g>a) p.(Asp67Asn) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 353.86 - GD: 0.00) Tolerated (score: 0.51) Polymorphism (p-value: 1)
exon 2 c.221G>A r.(221g>a) p.(Arg74His) Substitution Substitution Substitution (missense) Non-pathogenic Likely benign Unknown Positive MAF not reported gives 103% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 353.86 - GD: 0.00) Tolerated (score: 0.58) Polymorphism (p-value: 1)
exon 2 c.236_246del r.(236_246del) p.(Pro79Argfs*13) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 2 c.241C>T r.(241c>u) p.(Gln81*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 2 c.258dup r.(258dup) p.(Asn87Glnfs*9) Duplication Duplication Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs886042496 no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.258C>A r.(258c>a) p.? Substitution Substitution Substitution (silent) Unknown Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs146615896 no effect on splicing protein is not expressed
exon 2 c.265C>T r.(265c>u) p.(Arg89Cys) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs534192892 no effect on splicing protein is expressed Class C15 (GV: 109.21 - GD: 109.21) Deleterious (score: 0.01) Disease causing (prob: 1)
exon 2 c.266G>A r.(266g>a) p.(Arg89His) Substitution Substitution Substitution (missense) Presumably non-pathogenic Uncertain significance Classic infantile Positive MAF is less than 1% rs200586324 gives 43,5% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 109.21 - GD: 4.81) Deleterious (score: 0.02) Disease causing (p-value: 1)
exon 2 c.271G>A r.271g>a p.(Asp91Asn) Substitution Substitution Substitution (missense) Presumably non-pathogenic Likely benign Unknown (disease-associated) Positive MAF is over 1% rs1800299  lowers affinity for glycogen (GAA2) no effect on splicing protein is expressed Class C0 (GV: 65.47 - GD: 3.99) Tolerated (score: 0.08) Polymorphism (p-value: 0)
exon 2 c.271del r.(271del) p.(Asp91Ilefs*51) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.295_314del r.(295_314del) p.(Thr99Profs*40) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.307T>C r.(307u>c) p.(Cys103Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study loss of cryptic splice donor protein is expressed Class C0 (GV: 138.77 - GD: 66.46) Tolerated (score: 0.45) Disease causing (p-value: 1)
exon 2 c.307T>G r.(307u>g) p.(Cys103Gly) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported gives 1,5% (4MU) and 0% (glycogen) residual activity in expression study loss of cryptic splice donor protein is expressed Class C0 (GV: 138.77 - GD: 66.46) Tolerated (score: 0.45) Disease causing (p-value: 1)
exon 2 c.309C>G r.(309c>g) p.(Cys103Trp) substitution substitution Substitution (missense) Potentially less severe Unknown significance Unknown Positive MAF is less than 1% rs373307393 0% residual activity in GAA expression construct no effect on splicing protein is expressed Class C15 (GV: 138.77 - GD: 141.90) Deleterious (score: 0.02) Disease causing (prob: 1)
exon 2 c.309C>A r.(309c>a) p.(Cys103*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 2 c.317G>A r.(317g>a) p.(Arg106His) Substitution Substitution Substitution (missense) potentially less severe Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs772534106 no effect on splicing protein is expressed Class C0 (GV: 54.02 - GD: 5.07) Deleterious (score: 0.02) Disease causing (prob: 1)
exon 2 c.322T>G r.(322u>g) p.(Cys108Gly) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Unknown MAF not reported 8,2% residual activity and affects secretion & processing in expression study new cryptic splice donor unknown Class C0 (GV: 195.55 - GD: 75.02) Tolerated (score: 0.07) Disease causing (p-value: 1)
exon 2 c.323G>A r.(323g>a) p.(Cys108Ser) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 195.55 - GD: 32.43) Deleterious (score: 0.03) Disease causing (p-value: 1)
exon 2 c.323G>C r.(323g>c) p.(Cys108Ser) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 195.55 - GD: 61.25) Tolerated (score: 0.08) Disease causing (prob: 1)
exon 2 c.324T>C r.324u>c p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800300 no effect on splicing protein is expressed
exon 2 c.340_341insT r.(340_341insu) p.(Lys114Ilefs*32) Insertion Insertion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 2 c.343C>T r.(343c>u) p.(Gln115*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Childhood or Adult Negative MAF not reported new cryptic splice donor protein is not expressed
exon 2 c.352C>T r.(352c>u) p.(Gln118*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no protein on western blot no effect on splicing no endogeneous protein on western blot protein is not expressed
exon 2 c.363G>A r.(363g>a) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 2 c.364A>G r.(364a>g) p.(Met122Val) Substitution Substitution Substitution (missense) Less severe Uncertain significance Unknown (disease-associated) Unknown MAF not reported new cryptic splice donor unknown Class C0 (GV: 139.69 - GD: 0.00) Tolerated (score: 0.75) Polymorphism (p-value: 1)
exon 2 c.365del r.(365del) p.(Met122Argfs*20) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported rs786204661 no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.365T>A r.(365u>a) p.(Met122Lys) Substitution Substitution Substitution (missense) unknown Uncertain significance Unknown (found only in NBS) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 139.69 - GD: 12.95) Tolerated (score: 0.25) Polymorphism (prob: 1)
exon 2 c.377G>A r.(377g>a) p.(Trp126*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 2 c.378G>A r.(378g>a) p.(Trp126*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported loss of cryptic splice donor protein is not expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 3 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 2 c.379_380del r.(379_380del) p.(Cys127Leufs*18) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 2 c.380G>A r.(380g>a) p.(Cys127Tyr) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported strengthens a cryptic splice donor site unknown Class C0 (GV: 201.58 - GD: 19.40) Tolerated (score: 0.11) Disease causing (prob: 1)
exon 2 c.380G>T r.(380g>u) p.(Cys127Phe) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported 1,5% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 201.58 - GD: 26.66) Tolerated (score: 0.09) Disease causing (p-value: 1)
exon 2 c.397T>G r.(397u>g) p.(Tyr133Asp) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C55 (GV: 21.61 - GD: 157.87) Deleterious (score: 0) Disease causing (prob: 0.986)
exon 2 c.399C>A r.(399c>a) p.(Tyr133*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 2 c.421C>A r.(421c>a) p.(Leu141Met) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 102.84 - GD: 0.00) Tolerated (score: 0.19) Polymorphism (p-value: 0.89)
exon 2 c.424_440del r.(424_440del) p.(Ser142Lleufs*29) Deletion Deletion Frameshift Very severe Pathogenic Unknown (found only in NBS) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.437del r.(437del) p.(Met146Argfs*7) Deletion Deletion Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.444C>G r.(444c>g) p.(Tyr148*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 2 c.445A>C r.(445a>c) p.(Thr149Pro) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 158.11 - GD: 23.81) Tolerated (score: 0.26) Polymorphism (prob: 0.751)
exon 2 c.447G>A r.(447g>a) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2289536 no effect on splicing protein is expressed
exon 2 c.460_465del r.(460_465del) p.(Arg154_Thr155del) Deletion Deletion Deletion Unknown Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 2 c.461G>C r.(461g>c) p.(Arg154Pro) Substitution Substitution Substitution (missense) Less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 42.81 - GD: 69.18) Deleterious (score: 0.01) Disease causing (p-value: 0.986)
exon 2 c.461_469del r.(461_469del) p.(Arg154_Thr156del) Deletion Deletion Deletion Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0,5% residual activity and affects secretion & processing in expression study no effect on splicing - in frame product protein is expressed
exon 2 c.482_483del r.(482_483del) p.(Pro161Glnfs*15) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs764750389 no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.483dup r.(483dup) p.(Lys162Glnfs*15) Duplication Duplication Frameshift Very severe Uncertain significance Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 2 c.484A>C r.(484a>c) p.(Lys162Gln) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Unknown MAF not reported strenghens a cryptic splice acceptor unknown Class C0 (GV: 38.73 - GD: 19.90) Tolerated (score: 0.07) Polymorphism (prob: 1)
exon 2 c.502C>T r.(502c>u) p.(Arg168Trp) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs777473001 no effect on splicing protein is expressed Class C0 (GV: 115.59 - GD: 38.50) Deleterious (score: 0.04) Polymorphism (prob: 0.995)
exon 2 c.503G>A r.(503g>a) p.(Arg168Gln) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Childhood Unknown MAF is less than 1% rs376685205 new cryptic splice acceptor unknown Class C0 (GV: 115.59 - GD: 0.00) Tolerated (score: 0.41) Polymorphism (p-value: 1)
exon 2 c.503G>C r.(503g>c) p.(Arg168Pro) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Childhood Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 115.59 - GD: 53.19) Tolerated (score: 0.14) Polymorphism (p-value: 0.997)
exon 2 c.505C>A r.(505c>a) p.(Leu169Met) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 0.00 - GD: 14.30) Deleterious (score: 0) Disease causing (prob: 0.822)
exon 2 c.506T>C r.(506u>c) p.(Leu169Pro) Substitution Substitution Substitution (missense) Unknown Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (p-value: 1)
exon 2 c.510C>T r.(510c>u) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
exon 2 c.517_519del r.(517_519del) p.(Met173del) deletion deletion deletion Potentially less severe Likely pathogenic Childhood Positive MAF not reported no effect on splicing - causes an in frame product protein is expressed
exon 2 c.525del r.(525del) p.(Glu176Argfs*45) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs386834235   no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 2 c.525_526del r.(525_526del) p.(Asn177Profs*11) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs767882689 no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 2 c.532C>T r.(532c>u) p.(Arg178Cys) Substitution Substitution Substitution (missense) Non-pathogenic Likely benign Unknown Positive MAF is less than 1% gives 134% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 179.53 - GD: 0.00) Tolerated (score: 0.15) Disease causing (p-value: 1)
exon 2 c.533G>A r.(533g>a) p.(Arg178His) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs762267535 no effect on splicing protein is expressed Class C0 (GV: 179.53 - GD: 4.81) Tolerated (score: 0.12) Disease causing (p-value: 1)
exon 2 c.541_545del r.(541_545del) p.(Phe181Aspfs*6) Deletion Deletion Frameshift very severe Pathogenic Classic infantile Unknown MAF not reported weakens exon 2 splice donor site - causes an out of frame product unknown
exon 2 c.546G>A r.[(546g>a), r.(spl?)] p.[(=), p.?] Substitution Substitution/ Splicing (splice donor site) Substitution (silent), Insertion Potentially mild Likely pathogenic Adult Unknown MAF is less than 1% rs143523371 weakens exon 2 splice donor unknown
exon 2 c.546G>T r.[-32_546del,546g>u,546g>u; 546_547ins546+1_546+184] p.[=,0, Ile183Valfs*67] Substitution Substitution/ Splicing (splice donor site) Substitution (silent), Insertion Potentially mild Pathogenic Childhood or Adult Unknown MAF not reported causes partial inclusion of intron 2 weakens exon 2 splice donor detection of leaky wildtype splicing unknown
exon 2 c.546G>C r.[(546g>c), r.(spl?)] p.[(=), p.?] Substitution Substitution/ Splicing (splice donor site) Substitution (silent), Insertion Potentially mild Likely pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 2 splice donor unknown
intron 2 c.546+1G>T r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 2 splice donor unknown
intron 2 c.546+2T>C r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot loss of exon 2 splice donor no endogeneous protein on western blot unknown
intron 2 c.546+2_546+5del r.spl p.? Deletion Deletion/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot loss of exon 2 splice donor and new cryptic splice acceptor no endogeneous protein on western blot unknown
intron 2 c.546+5G>T r.(spl?) p.? Substitution Substitution (silent), Insertion No category Unknown Uncertain significance Unknown (found only in NBS) Unknown MAF is less than 1% rs756024023 weakens exon 2 splice donor and new cryptic splice donor unknown
intron 2 c.546+24G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
intron 2 c.546+45G>C r.(=) p.? Substitution Substitution (intron variant) No category Unknown Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 2 c.546+293G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs34746710 no effect on splicing protein is expressed
intron 2 c.547-243C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs8065426 no effect on splicing protein is expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 4 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
intron 2 c.547-238T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12452263 no effect on splicing protein is expressed
intron 2 c.547-67C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is over 1% rs8069491 no effect on splicing protein is expressed
intron 2 c.547-39T>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is over 1% rs12452721 loss of cryptic splice donor protein is expressed
intron 2 c.547-4C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs3816256 no effect on splicing protein is expressed
intron 2 c.547-1G>C r.spl p.? substitution Substitution/ Splicing (splice acceptor site) No category very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 3 splice acceptor site unknown
exon 3 c.568C>T r.(568c>u) p.(Arg190Cys) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF is less than 1% rs771258854 generates a new cryptic splice donor site unknown Class C25 (GV: 97.59 - GD: 154.97) Deleterious (score: 0.04) Disease causing (prob: 1)
exon 3 c.569G>A r.(569g>a) p.(Arg190His) Substitution Substitution Substitution (missense) Less severe Uncertain significance Childhood Positive MAF is less than 1% rs528367092 3,9% residual activityand affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 97.59 - GD: 15.20) Tolerated (score: 0.12) Disease causing (p-value: 1)
exon 3 c.572A>G r.(572a>g) p.(Tyr191Cys) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported gives 0,6% residual activity in expression study no effect on splicing protein is expressed Class C55 (GV: 21.61 - GD: 191.71) Deleterious (score: 0) Disease causing (p-value: 0.998)
exon 3 c.573C>A r.(573c>a) p.(Tyr191*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 3 c.596A>G r.(596a>g) p.(His199Arg) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Unknown Positive MAF is over 1% rs528367092 no effect on splicing protein is expressed Class C0 (GV: 113.73 - GD: 0.00) Tolerated (score: 0.84) Polymorphism (p-value: 1)
exon 3 c.623T>C r.(623u>c) p.(Leu208Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 21.82 - GD: 95.38) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 3 c.634G>T r.(634g>u) p.(Glu212*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 3 c.642C>T r.642c>u p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800301 no effect on splicing protein is expressed
exon 3 c.650C>T r.(650c>u) p.(Pro217Leu) Substitution Substitution Substitution (missense) Less severe Uncertain significance Classic infantile Positive MAF not reported 13,3% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C15 (GV: 90.16 - GD: 79.62) Deleterious (score: 0.03) Disease causing (p-value: 1)
exon 3 c.655G>A r.(655g>a) p.(Gly219Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs370950728 gives 0,5% (4MU) and 0% (glycogen) residual activity in expression study no effect on splicing endogenous protein on western blot protein is expressed Class C25 (GV: 60.00 - GD: 97.30) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 3 c.658G>T r.(658g>u) p.(Val220Leu) Substitution Substitution Substitution (missense) Non-pathogenic Likely benign Unknown Positive MAF is less than 1% gives 100% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 108.52 - GD: 0.00) Tolerated (score: 1) Polymorphism (p-value: 1)
exon 3 c.664G>A r.(664g>a) p.(Val222Met) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% gives 98% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 30.92 - GD: 0.00) Deleterious (score: 0.02) Disease causing (p-value: 0.832)
exon 3 c.665T>G r.(665u>g) p.(Val222Gly) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 30.92 - GD: 109.55) Deleterious (score: 0) Disease causing (prob: 1)
exon 3 c.668G>A r.668g>a p.(Arg223His) Substitution Substitution Substitution (missense) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1042395 no effect on splicing protein is expressed Class C0 (GV: 102.71 - GD: 0.00) Tolerated (score: 0.07) Polymorphism (p-value: 1)
exon 3 c.670C>T r.(670c>u) p.(Arg224Trp) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Classic infantile or Childhood Positive MAF is less than 1% rs757700700 no effect on splicing protein is expressed Class C25 (GV: 54.02 - GD: 101.29) Deleterious (score: 0) Polymorphism (p-value: 0.886)
exon 3 c.671G>C r.(671g>c) p.(Arg224Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C15 (GV: 54.02 - GD: 67.63) Deleterious (score: 0.02) Disease causing (p-value: 1)
exon 3 c.671G>A r.(671g>a) p.(Arg224Gln) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Adult Positive MAF is less than 1% rs200210219 0,7% residual activity and affects secretion & processing in expression study loss of cryptic splice acceptor protein is expressed Class C0 (GV: 54.02 - GD: 0.00) Deleterious (score: 0.04) Disease causing (p-value: 1)
exon 3 c.685_686insCGGC r.(685_686inscggc) p.(Arg229Profs*102) Insertion Insertion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 3 c.686G>C r.(686g>c) p.(Arg229Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported rs776509432 no effect on splicing protein is expressed Class C0 (GV: 157.63 - GD: 23.81) Tolerated (score: 0.12) Polymorphism (prob: 1)
exon 3 c.692T>C r.(692u>c) p.(Leu231Pro) Substitution Substitution/ Splicing (splice donor site) Substitution (missense) very severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported strengthens exon 3 splice donor site unknown Class C65 (GV: 4.86 - GD: 95.38) Deleterious (score: 0) Disease causing (prob: 1)
intron 3 c.692+1G>C r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Unknown (disease-associated) Unknown MAF is less than 1% rs773281453 loss of exon 3 splice donor unknown
intron 3 c.692+1G>T r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 3splice donor site unknown
intron 3 c.692+1G>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 3 splice donor unknown
intron 3 c.692+5G>T r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) No category Less severe Pathogenic Childhood or adult Unknown MAF is less than 1% rs763027848 loss of exon 3 splice donor unknown
exon 3 c.691C>T r.(691c>u) p.(Arg190Cys) Substitution Substitution (splice donor site) Substitution (missense) very severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported no effect on splicing unknown
intron 3 c.692+38C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304848 generates a new cyptic splice donor site unknown
intron 3 c.692+144A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304847 no effect on splicing protein is expressed
intron 3 c.692+509T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs8082405 no effect on splicing protein is expressed
intron 3 c.692+674G>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs8078350 no effect on splicing protein is expressed
intron 3 c.692+751T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs8068051 no effect on splicing protein is expressed
intron 3 c.693-586G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs112308142 no effect on splicing protein is expressed
intron 3 c.693-585T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs8068555 no effect on splicing protein is expressed
intron 3 c.693-559C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12602422 no effect on splicing protein is expressed
intron 3 c.693-491G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12948631 no effect on splicing protein is expressed
intron 3 c.693-441C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12602440 loss of a cryptic splice acceptor site unknown

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 5 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
intron 3 c.693-434C>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12941269 no effect on splicing protein is expressed
intron 3 c.693-414C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12941289 loss of a cryptic splice acceptor site unknown
intron 3 c.693-413A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12937590 loss of a cryptic splice acceptor site unknown
intron 3 c.693-216T>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs11150844 no effect on splicing protein is expressed
intron 3 c.693-94C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs79849256 no effect on splicing protein is expressed
intron 3 c.693-78C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs74003611 no effect on splicing protein is expressed
intron 3 c.693-49C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs78855075 no effect on splicing protein is expressed
intron 3 c.693-2A>C r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 4 splice acceptor site unknown
intron 3 c.693-1G>C r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 5 splice accepter site unknown
exon 4 c.701C>G r.(701c>g) p.(Thr234Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 1,6% residual activity in expression study and affects secretion & processing in ... no effect on splicing protein is expressed Class C0 (GV: 114.06 - GD: 5.07) Tolerated (score: 0.07) Disease causing (p-value: 1)
exon 4 c.701C>A r.(701c>a) p.(Thr234Lys) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported 2,7% residual activity in expression study and affects secretion & processing in ... no effect on splicing protein is expressed Class C0 (GV: 114.06 - GD: 0.00) Tolerated (score: 0.36) Disease causing (p-value: 1)
exon 4 c.705G>A r.(705g>a) p.(=) Substitution Substitution Substitution (silent) Unknown Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs2304846 no effect on splicing protein is expressed
exon 4 c.710C>T r.(710c>u) p.(Ala237Val) Substitution Substitution Substitution (missense) Unknown Uncertain significance Adult Positive MAF is less than 1% rs121907944 no effect on splicing protein is expressed Class C0 (GV: 170.54 - GD: 35.60) Tolerated (score: 0.19) Disease causing (p-value: 0.982)
exon 4 c.715_716del r.(715_716del) p.(Leu239Valfs*90) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 4 c.716del r.(716del) p.(Leu239Argfs*29) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 4 c.719T>C r.(719u>c) p.(Phe240Ser) Substitution Substitution Substitution (missense) Unknown Uncertain significance Adult Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 115.75 - GD: 73.35) Deleterious (score: 0.05) Disease causing (p-value: 0.956)
exon 4 c.722_723del r.(722_723del) p.(Phe241Cysfs*88) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 4 c.725C>T r.(725c>u) p.(Ala242Val) Substitution Substitution Substitution (missense) Potentially mild Uncertain significance Unknown Positive MAF is less than 1% rs745861849 gives 14% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 138.12 - GD: 35.60) Deleterious (score: 0.03) Disease causing (p-value: 1)
exon 4 c.730C>T r.(730c>u) p.(Gln244*) substitution substitution Substitution (nonsense) very severe Pathogenic Classic infantile Unknown MAF not reported weakens a cryptic splice acceptor site unknown
exon 4 c.736del r.(736del) p.(Leu246Phefs*22) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs886043920 no effect on splicing - causes an out of frame product protein is not expressed
exon 4 c.737T>G r.(737u>g) p.(Leu246Arg) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 30.92 - GD: 87.80) Deleterious (score: 0) Disease causing (p-value: 1)
exon 4 c.742del r.(742del) p.(Leu248Profs*20) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 4 c.743T>G r.(743u>g) p.(Leu248Arg) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 4.86 - GD: 97.59) Deleterious (score: 0) Disease causing (p-value: 0.995)
exon 4 c.743T>C r.(743u>c) p.(Leu248Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 4.86 - GD: 95.38) Deleterious (score: 0) Disease causing (p-value: 1)
exon 4 c.[752C>T; c.761C>T] r.[(752c>u); (761c>u)] p.[(Ser251Leu); (Ser254Leu)] Substitution Substitution Substitution (missense) Presumably non-pathogenic Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs200856561 no effect on splicing protein is expressed
exon 4 c.756_757insT r.(756_757insu) p.(Pro253Serfs*77) insertion insertion Frameshift very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported strenghens a cryptic splice acceptor - causes an out of frame product unknown
exon 4 c.759del r.(759del) p.(Ser254Argfs*14) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 4 c.763C>T r.(763c>u) p.(Gln255*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 4 c.766_784del r.(766_784del) p.(Tyr256Serfs*6) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported rs1223685051 loss of cryptic splice acceptor site - causes an out of frame product unknown
exon 4 c.766_785delinsC r.(766_785delinsc) p.(Tyr256Argfs*6) Deletion/ insertion Deletion/ insertion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 4 c.768dup r.(768dup) p.(Ile257Tyrfs*73) Duplication Duplication Frameshift Very severe Uncertain significance Unknown Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 4 c.776G>T r.(776g>u) p.(Gly259Val) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 109.55) Deleterious (score: 0) Disease causing (p-value: 1)
exon 4 c.781G>A r.(781g>a) p.(Ala261Thr) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs543360994 0,43% residual activity, no effect on processing and secretion no effect on splicing protein found on western blot protein is expressed Class C0 (GV: 61.14 - GD: 28.88) Tolerated (score: 0.13) Disease causing (prob: 0.844)
exon 4 c.784G>A r.(784g>a) p.(Glu262Lys) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs201896815 no effect on splicing protein is expressed Class C15 (GV: 29.27 - GD: 51.63) Deleterious (score: 0.02) Disease causing (p-value: 0.998)
exon 4 c.784G>C r.(784g>c) p.(Glu262Gln) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 29.27 - GD: 0.00) Tolerated (score: 0.14) Disease causing (prob: 0.994)
exon 4 c.794del r.(794del) p.(Ser265Ilefs*3) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 4 c.796C>T r.(796c>u) p.(Pro266Ser) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Classic infantile Positive MAF not reported gives 18% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 99.44 - GD: 0.00) Tolerated (score: 0.85) Disease causing (p-value: 0.603)
exon 4 c.796C>A r.(796c>a) p.(Pro266Thr) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Childhood Unknown MAF not reported loss of a cryptic splice acceptor site unknown Class C0 (GV: 99.44 - GD: 28.88) Tolerated (score: 0.06) Disease causing (prob: 0.584)
exon 4 c.799_803delinsA r.(799_803delinsa) p.(Leu267Serfs*46) Deletion/ insertion Deletion/ insertion Frameshift very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of cryptic splice accepter site - causes an out of frame product unknown
exon 4 c.811A>G r.(811a>g) p.(Thr271Ala) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Unknown (found only in NBS) Positive MAF not reported gives 83,6% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 137.69 - GD: 0.00) Tolerated (score: 1) Polymorphism (p-value: 0.983)

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 6 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 4 c.827_845del r.(827_845del) p.(Ile276Thrfs*32) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 4 c.829_851del r.(829_851del) p.(Thr277Alafs*45) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 4 c.836G>A r.(836g>a) p.(Trp279*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 4 c.837G>C r.(837g>c) p.(Trp279Cys) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs1364351022 no effect on splicing protein is expressed Class C45 (GV: 39.66 - GD: 196.12) Deleterious (score: 0) Disease causing (prob: 1)
exon 4 c.841C>T r.(841c>u) p.(Arg281Trp) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs142967546 no effect on splicing protein is expressed Class C0 (GV: 95.37 - GD: 47.30) Deleterious (score: 0.02) Disease causing (prob: 0.988)
exon 4 c.844G>C r.(844g>c) p.(Asp282His) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 81.24) Deleterious (score: 0) Disease causing (p-value: 1)
exon 4 c.852G>A r.(852g>a) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs142626724 no effect on splicing protein is expressed
exon 4 c.853C>T r.(853c>u) p.(Pro285Ser) Substitution Substitution Substitution (missense) Less severe Uncertain significance Childhood or Adult Positive MAF not reported gives 4,8% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 93.73 - GD: 34.34) Deleterious (score: 0.04) Disease causing (p-value: 1)
exon 4 c.854C>G r.(854c>g) p.(Pro285Arg) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Childhood Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 93.73 - GD: 41.54) Deleterious (score: 0.03) Disease causing (p-value: 1)
intron 4 c.858+2T>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile or Childhood Negative MAF not reported no protein on western blot loss of exon 4 splice donor no endogeneous protein on western blot unknown
intron 4 c.858+5_858+6ins7 r.(spl?) p.? Insertion Insertion (intron variant) No category Unknown Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 4 c.858+6G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 4 c.858+17_858+23del r.(=) p.? Deletion Deletion (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 4 c.858+20dup r.(=) p.? Insertion Insertion (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported missplicing around exon 7 resulting in a skip of exon 7 no effect on splicing protein is expressed
intron 4 c.858+21C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 4 c.858+17_858+23dup r.(=) p.? Insertion Insertion (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 4 c.858+30T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304845 no effect on splicing protein is expressed
intron 4 c.858+37C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 4 c.859-2A>T r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 5 splice acceptor unknown
exon 5 c.861C>T r.(861c>u) p.(=) Substitution Substitution Substitution (silent) Potentially less severe Uncertain significance Childhood Positive MAF is less than 1% rs778580823 no effect on splicing protein is expressed
exon 5 c.868A>G r.(868a>g) p.(Asn290Asp) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% gives 71% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 90.16 - GD: 22.92) Tolerated (score: 0.31) Disease causing (p-value: 0.957)
exon 5 c.871C>T r.(871c>u) p.(Leu291Phe) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs773417785 gives 0,7% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 14.30 - GD: 21.28) Deleterious (score: 0.02) Disease causing (p-value: 0.815)
exon 5 c.872T>A r.(872u>a) p.(Leu291His) Substitution Substitution Substitution (missense) Less severe Uncertain significance Unknown Positive MAF not reported 2% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C45 (GV: 14.30 - GD: 86.34) Deleterious (score: 0) Disease causing (p-value: 0.908)
exon 5 c.872T>C r.(872u>c) p.(Leu291Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0,7% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C45 (GV: 14.30 - GD: 86.59) Deleterious (score: 0) Disease causing (p-value: 1)
exon 5 c.875A>G r.(875a>g) p.(Tyr292Cys) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 193.72) Deleterious (score: 0) Disease causing (p-value: 0.997)
exon 5 c.876C>G r.(876c>g) p.(Tyr292*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Classic infantile Negative MAF not reported 0% residual activity no effect on splicing no protein on western blot protein is not expressed
exon 5 c.877G>A r.(877g>a) p.(Gly293Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs121907945 new cryptic splice acceptor endogenous protein on western blot unknown Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 1)
exon 5 c.878G>T r.(878g>u) p.(Gly293Val) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 109.55) Deleterious (score: 0) Disease causing (prob: 1)
exon 5 c.883C>A r.(883c>a) p.(His295Asn) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs751639773 no effect on splicing protein is expressed Class C0 (GV: 94.34 - GD: 68.35) Tolerated (score: 0.18) Disease causing (prob: 1)
exon 5 c.885C>G r.(885c>g) p.(His295Gln) Substitution Substitution Substitution (missense) Potentially mild Uncertain significance Adult Unknown MAF not reported new cryptic splice acceptor unknown Class C0 (GV: 94.34 - GD: 24.08) Tolerated (score: 0.19) Disease causing (p-value: 0.869)
exon 5 c.893A>C r.(893a>c) p.(Tyr298Ser) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 37.91 - GD: 121.85) Deleterious (score: 0.01) Disease causing (p-value: 0.944)
exon 5 c.896T>G r.(896u>g) p.(Leu299Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C45 (GV: 21.82 - GD: 96.69) Deleterious (score: 0.01) Disease causing (p-value: 0.999)
exon 5 c.896T>C r.(896u>c) p.(Leu299Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C35 (GV: 21.82 - GD: 95.38) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 5 c.915G>A r.(915g>a) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% loss of cryptic splice donor protein is expressed
exon 5 c.917C>T r.(917c>u) p.(Ser306Leu) Substitution Substitution Substitution (missense) Presumably non-pathogenic Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs138097673 no effect on splicing protein is expressed Class C0 (GV: 167.35 - GD: 0.00) Tolerated (score: 0.42) Polymorphism (p-value: 1)
exon 5 c.921A>T r.921a>u p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800303 no effect on splicing protein is expressed
exon 5 c.923A>C r.(923a>c) p.(His308Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 46.75 - GD: 33.14) Tolerated (score: 0.13) Disease causing (p-value: 1)
exon 5 c.923A>T r.(923a>u) p.(His308Leu) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 46.75 - GD: 73.51) Tolerated (score: 0.13) Disease causing (p-value: 1)
exon 5 c.925G>A r.(925g>a) p.(Gly309Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs543300039 affects processing in expression study new weak cryptic splice acceptor endogenous protein on western blot unknown Class C25 (GV: 55.27 - GD: 95.76) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 5 c.929T>G r.(929u>g) p.(Val310Gly) Substitution Substitution Substitution (missense) Less severe Uncertain significance Unknown Positive MAF is less than 1% rs763091901 no effect on splicing protein is expressed Class C35 (GV: 28.68 - GD: 109.55) Deleterious (score: 0) Disease causing (p-value: 1)

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 7 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 5 c.930_932del r.(930_932del) p.(Phe311del) deletion deletion deletion Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - causes an in frame product protein is expressed
exon 5 c.935T>G r.(935u>g) p.(Leu312Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 60.98 - GD: 89.93) Deleterious (score: 0.01) Disease causing (p-value: 0.987)
exon 5 c.942C>A r.(942c>a) p.Asn314Lys substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 93.88) Deleterious (score: 0) Disease causing (prob: 1)
exon 5 c.947A>T r.(947a>u) p.(Asn316Ile) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 165.22 - GD: 16.18) Tolerated (score: 0.08) Disease causing (p-value: 1)
exon 5 c.947A>G r.(947a>g) p.(Asn316Ser) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 165.22 - GD: 6.18) Tolerated (score: 0.39) Disease causing (prob: 0.998)
exon 5 c.950C>T r.(950c>u) p.(Ala317Val) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs1425709688 no effect on splicing protein is expressed Class C0 (GV: 125.75 - GD: 47.48) Tolerated (score: 0.13) Disease causing (prob: 1)
exon 5 c.953T>C r.(953u>c) p.(Met318Thr) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF is less than 1% rs121907936 no effect on splicing protein is expressed Class C0 (GV: 89.28 - GD: 0.00) Tolerated (score: 0.42) Disease causing (p-value: 0.998)
exon 5 c.953T>A r.(953u>a) p.(Met318Lys) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Childhood Positive MAF not reported 3,2% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 89.28 - GD: 44.44) Deleterious (score: 0.03) Disease causing (p-value: 1)
exon 5 c.955_955+1ins21 r.[(955_956ins21), (spl?)] p.? Insertion Insertion/ Splicing (splice donor site) No category Unknown Likely pathogenic Unknown (disease-associated) Unknown MAF not reported unknown - in frame product unknown
intron 5 c.955+1G>A r.spl p.? substitution Substitution/ Splicing (splice donor site) No category very severe Pathogenic Classic infantile Unknown MAF is less than 1% rs1403691329 loss of exon 6 splice donor site unknown
intron 5 c.955+155C>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs9901190 no effect on splicing protein is expressed
intron 5 c.955+167C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs77717164 no effect on splicing protein is expressed
intron 5 c.956-107G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2241888 no effect on splicing protein is expressed
intron 5 c.955+2T>G r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Uncertain significance Unknown (disease-associated) Unknown MAF not reported loss of exon 5 splice donor unknown
intron 5 c.955+12G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2252455 no effect on splicing protein is expressed
intron 5 c.956-84C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2241887 no effect on splicing protein is expressed
exon 6 c.971C>T r.(971c>u) p.(Pro324Leu) Substitution Substitution Substitution (missense) Less severe Uncertain significance Childhood Positive MAF is less than 1% rs750030887 no effect on splicing protein is expressed Class C0 (GV: 107.83 - GD: 63.55) Deleterious (score: 0.04) Disease causing (p-value: 1)
exon 6 c.971dup r.(971dup) p.(Pro324Argfs*68) duplication duplication Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 6 c.982_988del r.(982_988del) p.(Leu328Glyfs*62) Deletion Deletion Frameshift very severe Pathogenic Classic infantile Unknown MAF not reported loss of cryptic splice acceptor site - causes an out of frame product unknown
exon 6 c.983T>C r.(983u>c) p.(Leu328Pro) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 92.35 - GD: 28.88) Deleterious (score: 0.02) Disease causing (prob: 1)
exon 6 c.988T>G r.(988u>g) p.(Trp330Gly) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 37.11 - GD: 146.93) Deleterious (score: 0) Disease causing (p-value: 1)
exon 6 c.989G>A r.(989g>a) p.(Trp330*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 6 c.994_995insTT r.(994_995insuu) p.(Ser332Phefs*61) insertion insertion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 6 c.998C>A r.(998c>a) p.(Thr333Lys) Substitution Substitution Substitution (missense) Unknown Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 144.57 - GD: 8.11) Tolerated (score: 0.13) Polymorphism (p-value: 1)
exon 6 c.1000G>A r.(1000g>a) p.(Gly334Ser) Substitution Substitution Substitution (missense) Unknown Uncertain significance Childhood Positive MAF not reported loss of cryptic splice donor protein is expressed Class C0 (GV: 79.35 - GD: 6.18) Tolerated (score: 0.05) Disease causing (p-value: 1)
exon 6 c.1000G>T r.(1000g>u) p.(Gly334Ser) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Unknown MAF not reported generates a new cyptic splice donor site unknown Class C0 (GV: 79.35 - GD: 6.18) Tolerated (score: 0.05) Disease causing (prob: 1)
exon 6 c.1003G>A r.(1003g>a) p.(Gly335Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF is less than 1% rs202095215 0,8% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 1)
exon 6 c.1004G>A  r.(1004g>a ) p.(Gly335Glu) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported 0,2% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.85) Deleterious (score: 0) Disease causing (p-value: 1)
exon 6 c.1004_1005dup r.(1004_1005dup) p.(Ile336Glyfs*57) Duplication Duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 6 c.1040C>G r.(1040c>g) p.(Pro347Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported 1% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 95.38 - GD: 46.14) Tolerated (score: 0.13) Disease causing (p-value: 1)
exon 6 c.1047del r.(1047del) p.(Ser349Argfs*43) deletion deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 6 c.1048G>A r.(1048g>a) p.(Val350Met) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs200412003 no effect on splicing protein is expressed Class C0 (GV: 28.68 - GD: 0.00) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 6 c.1051del r.(1051del) p.(Val351Cysfs*41) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 6 c.1054C>T r.(1054c>u) p.(Gln352*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Unknown (found only in NBS) Negative MAF not reported rs764355476 no effect on splicing protein is not expressed
exon 6 c.1057C>T r.(1057c>u) p.(Gln353*) substitution substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 6 c.1057del r.(1057del) p.(Gln353Serfs*39) deletion deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 6 c.1062C>G r.(1062c>g) p.(Tyr354*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 6 c.1064T>C r.(1064u>c) p.(Leu355Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile or Childhood Positive MAF is less than 1% rs766074609 no effect on splicing endogenous protein on western blot protein is expressed Class C0 (GV: 120.48 - GD: 28.88) Tolerated (score: 0.08) Disease causing (p-value: 1)
exon 6 c.1075G>A r.[1075g>a, 1072_1075del] p.[(Gly359Arg), (Val358Aspfs*33)] Substitution Substitution/ Splicing (splice donor site) Substitution (missense), Frameshift Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported causes skip of the last 4 bp of exon 6 - 54% residual activity and affects secre ... loss of exon 6 splice donor detection of leaky wildtype splicing unknown Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 1)
exon 6 c.1075G>T r.[(1075g>u), r.(spl?)] p.[(Ily359*), p.?] Substitution Substitution/ Splicing (splice donor site) Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot weakens exon 6 splice donor no endogeneous protein on western blot protein is not expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 8 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
intron 6 c.1075+13C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is over 1% rs41292402 no effect on splicing protein is expressed
intron 6 c.1076-22T>G r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) Insertion Potentially mild Pathogenic Childhood Unknown MAF is less than 1% rs762260678 new cryptic splice acceptor unknown
intron 6 c.1076-1G>A r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 7 splice acceptor unknown
intron 6 c.1076-1G>C r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 7 splice acceptor unknown
exon 7 c.1080C>G r.(1080c>g) p.(Tyr360*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (found only in NBS) Negative MAF not reported no effect on splicing protein is not expressed
exon 7 c.1082C>T r.(1082c>u) p.(Pro361Leu) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs755253527 3,9% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (p-value: 1)
exon 7 c.1082C>A r.(1082c>a) p.(Pro361Arg) Substitution Substitution Substitution (missense) potentially less severe Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs755253527 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 102.71) Deleterious (score: 0) Disease causing (prob: 1)
exon 7 c.1099T>C r.(1099u>c) p.(Trp367Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 176.58 - GD: 21.04) Tolerated (score: 0.13) Disease causing (p-value: 1)
exon 7 c.1099T>G r.(1099u>g) p.(Trp367Gly) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 176.58 - GD: 29.38) Tolerated (score: 0.36) Disease causing (prob: 1)
exon 7 c.1100G>A r.(1100g>a) p.(Trp367*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 7 c.1101G>A r.(1101g>a) p.(Trp367*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 7 c.1106T>C r.(1106u>c) p.(Leu369Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 3,1% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 4.86 - GD: 95.38) Deleterious (score: 0) Disease causing (p-value: 1)
exon 7 c.1106T>A r.(1106u>a) p.(Leu369Gln) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 4.86 - GD: 108.57) Deleterious (score: 0.01) Disease causing (prob: 1)
exon 7 c.1108G>A r.(1108g>a) p.(Gly370Ser) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C55 (GV: 0.00 - GD: 55.27) Deleterious (score: 0) Disease causing (prob: 1)
exon 7 c.1109G>A r.(1109g>a) p.(Gly370Asp) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 93.77) Deleterious (score: 0) Disease causing (prob: 1)
exon 7 c.1114C>G r.(1114c>g) p.(His372Asp) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 81.24) Deleterious (score: 0) Disease causing (prob: 1)
exon 7 c.1114C>T r.(1114c>u) p.(His372Tyr) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 83.33) Deleterious (score: 0) Disease causing (prob: 1)
exon 7 c.1115A>T r.(1115a>u) p.(His372Leu) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 98.69) Deleterious (score: 0) Disease causing (p-value: 1)
exon 7 c.1118T>G r.(1118u>g ) p.(Leu373Arg) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Unknown MAF not reported new weak cryptic splice donor unknown Class C0 (GV: 112.44 - GD: 13.17) Deleterious (score: 0.04) Disease causing (p-value: 1)
exon 7 c.1120T>C r.(1120u>c) p.(Cys374Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 179.53) Deleterious (score: 0) Disease causing (p-value: 1)
exon 7 c.1121G>A r.(1121g>a) p.(Cys374Tyr) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 193.72) Deleterious (score: 0) Disease causing (prob: 1)
exon 7 c.1124G>T r.(1124g>u) p.(Arg375Leu) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs142752477 gives 0,3% residual activity in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 101.88) Deleterious (score: 0) Disease causing (p-value: 1)
exon 7 c.1124G>A r.(1124g>a) p.(Arg375His) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs142752477 no effect on splicing protein is expressed Class C25 (GV: 0.00 - GD: 28.82) Deleterious (score: 0) Disease causing (p-value: 1)
exon 7 c.1127_1130del r.(1127_1130del) p.(Trp376Serfs*15) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing - causes an out of frame product protein is expressed
exon 7 c.1128_1129delinsC r.(1128_1129delinsc) p.(Trp376Cysfs*16) Deletion/ insertion Deletion/ insertion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 7 c.1129G>C r.(1129g>c) p.(Gly377Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs752002666 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C15 (GV: 79.35 - GD: 69.17) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 7 c.1129G>A r.(1129g>a) p.(Gly377Ser) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 79.35 - GD: 6.18) Tolerated (score: 0.05) Disease causing (prob: 1)
exon 7 c.1134C>G r.(1134c>g) p.(Tyr378*) Substitution Substitution Substitution (nonsense) Very severe Uncertain significance Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 7 c.1143del r.(1143del) p.(Ala382Leufs*10) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs757458607 no effect on splicing - causes an out of frame product protein is not expressed
exon 7 c.1153del r.(1153del) p.(Arg385Alafs*7) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 7 c.1156C>T r.(1156c>u) p.(Gln386*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 7 c.1157dup r.(1157dup) p.(Val387Glyfs*119) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 7 c.1165del r.(1165del) p.(Glu389Argfs*3) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile or Childhood Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 7 c.1171A>G r.(1171a>g) p.(Met391Val) Substitution Substitution Substitution (missense) Presumably non-pathogenic Uncertain significance Unknown (disease-associated) Unknown MAF is less than 1% rs778634337 new weak cryptic splice donor unknown Class C15 (GV: 0.00 - GD: 20.52) Deleterious (score: 0) Disease causing (p-value: 0.995)
exon 7 c.1190C>T r.(1190c>u) p.(Pro397Leu) Substitution Substitution Substitution (missense) Less severe Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs776008078 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (p-value: 1)
exon 7 c.1192dup r.(1192dup) p.(Leu398Profs*108) Duplication Duplication Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 7 c.1192del r.(1192del) p.(Leu398Trpfs*42) deletion deletion Frameshift very severe Pathogenic Unknown (disease-associated) MAF is less than 1% rs1355323611 no effect on splicing - causes an out of frame product
exon 7 c.1193del r.(1193del) p.(Leu398Argfs*42) deletion Deletion/ Splicing (splice donor site) Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
intron 7 c.1194+2T>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 7 splice donor unknown
intron 7 c.1194+2T>C r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported weakens exon 7 splice donor unknown

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 9 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
intron 7 c.1194+5G>A r.(spl?) p.? Substitution Substitution (intron variant) No category less severe Uncertain significance Unknown (disease-associated) Unknown MAF not reported weakens exon 7 splice donor unknown
intron 7 c.1195-44C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
intron 7 c.1195-19_2190-20del r.spl p.? Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
intron 7 c.1195-15G>A r.(=) p.? Substitution Substitution (intron variant) No category Unknown Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs373840229 no effect on splicing protein is expressed
intron 7 c.1195-8G>A r.(spl?) p.? Substitution Substitution (intron variant) No category Unknown Uncertain significance Childhood or Adult Unknown MAF not reported loss of exon 8 splice acceptor unknown
intron 7 c.1195-2A>G r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF is less than 1% rs765360653 loss of exon 8 splice acceptor unknown
exon 8 c.1199_1210del r.(1199_1210del) p.(Val400_Asn403del) Deletion Deletion Deletion Very severe Likely pathogenic Classic infantile Unknown MAF not reported weakens exon 8 splice acceptor - in frame product unknown
exon 8 c.1201C>A r.(1201c>a) p.(Gln401Lys) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 148.91 - GD: 8.11) Tolerated (score: 1) Disease causing (prob: 0.999)
exon 8 c.1202A>G r.(1202a>g) p.(Gln401Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 5% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 148.91 - GD: 13.17) Tolerated (score: 0.76) Disease causing (p-value: 0.995)
exon 8 c.1203G>A r.1203g>a p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800304 no effect on splicing protein is expressed
exon 8 c.1204T>C r.(1204u>c) p.(Trp402Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 176.58 - GD: 21.04) Deleterious (score: 0.02) Disease causing (p-value: 1)
exon 8 c.1209C>G r.(1209c>g) p.(Asn403Lys) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 152.33 - GD: 8.11) Tolerated (score: 0.22) Disease causing (p-value: 0.893)
exon 8 c.1209C>A r.(1209c>a) p.(Asn403Lys) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing no effect on splicing protein is expressed Class C0 (GV: 152.33 - GD: 8.11) Tolerated (score: 0.22) Disease causing (prob: 0.893)
exon 8 c.1209del r.(1209del) p.(Asn403Lysfs*37) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 8 c.1210G>A r.(1210g>a) p.(Asp404Asn) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF is less than 1% rs141533320 no effect on splicing protein is expressed Class C0 (GV: 23.01 - GD: 0.00) Tolerated (score: 0.16) Disease causing (p-value: 1)
exon 8 c.1211A>G r.(1211a>g) p.(Asp404Gly) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 23.01 - GD: 77.99) Deleterious (score: 0.04) Disease causing (p-value: 1)
exon 8 c.1211A>C r.(1211a>c) p.(Asp404Ala) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C45 (GV: 23.01 - GD: 109.97) Deleterious (score: 0.01) Disease causing (prob: 1)
exon 8 c.1211A>T r.(1211a>u) p.(Asp404Val) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported rs886042961 no effect on splicing protein is expressed Class C45 (GV: 23.01 - GD: 133.10) Deleterious (score: 0) Disease causing (prob: 1)
exon 8 c.1212C>G r.(1212c>g) p.(Asp404Glu) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 23.01 - GD: 39.26) Deleterious (score: 0.02) Polymorphism (prob: 0.553)
exon 8 c.1214T>C r.(1214u>c) p.(Leu405Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 4.86 - GD: 95.38) Deleterious (score: 0) Disease causing (p-value: 1)
exon 8 c.1216G>A r.(1216g>a) p.(Asp406Asn) Substitution Substitution Substitution (missense) potentially less severe Uncertain significance Childhood Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 44.60 - GD: 11.33) Deleterious (score: 0.02) Disease causing (prob: 1)
exon 8 c.1219T>C r.(1219u>c) p.(Tyr407His) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported rs727503939 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 83.33) Deleterious (score: 0) Disease causing (prob: 0.998)
exon 8 c.1220A>G r.(1220a>g) p.(Tyr407Cys) Substitution Substitution Substitution (missense) potentially less severe Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs780674083 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 193.72) Deleterious (score: 0) Disease causing (prob: 1)
exon 8 c.1221C>A r.(1221c>a) p.(Tyr407*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 8 c.1221del r.1221del p.(Tyr407*) Deletion Deletion Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 8 c.1222A>G r.(1222a>g) p.(Met408Val) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs560575383 no effect on splicing protein is expressed Class C0 (GV: 101.00 - GD: 0.00) Tolerated (score: 0.69) Polymorphism (p-value: 0.992)
exon 8 c.1226_1227insG r.(1226_1227insg) p.(Asp409Glufs*97) insertion insertion frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 8 c.1229C>T r.(1229c>u) p.(Ser410Phe) Substitution Substitution Substitution (missense) Non-pathogenic Likely benign Unknown Positive MAF is less than 1% gives 111% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 154.10 - GD: 48.75) Deleterious (score: 0.05) Polymorphism (p-value: 1)
exon 8 c.1231del r.(1231del) p.(Arg411Glyfs*29) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 8 c.1239C>G r.(1239c>g) p.(Asp413Glu) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 170.55 - GD: 0.00) Tolerated (score: 0.8) Polymorphism (p-value: 0.992)
exon 8 c.1240T>C r.(1240u>c) p.(Phe414Leu) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported rs886042630 no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 21.82) Deleterious (score: 0) Disease causing (prob: 0.959)
exon 8 c.1241del r.(1241del) p.(Phe414Serfs*26) deletion deletion Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 8 c.1242C>A r.(1242c>a) p.(Phe414Leu) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 21.82) Deleterious (score: 0) Disease causing (prob: 0.52)
exon 8 c.1244C>T r.(1244c>u) p.(Thr415Met) Substitution Substitution Substitution (missense) potentially less severe Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs374842126 no effect on splicing protein is expressed Class C15 (GV: 57.75 - GD: 81.04) Deleterious (score: 0) Disease causing (prob: 0.937)
exon 8 c.1249A>C r.(1249a>c) p.(Asn417His) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 101.46 - GD: 14.57) Tolerated (score: 0.06) Disease causing (prob: 0.506)
exon 8 c.1256A>T r.1256a>u p.(Asp419Val) Substitution Substitution/ Splicing (exon variant) Substitution (missense), Deletion Potentially mild Likely pathogenic Unknown (disease-associated) Positive MAF not reported gives 21,3% residual activity in expression study - partial skip of exon 8 new cryptic splice donor detection of leaky wildtype splicing unknown Class C15 (GV: 99.09 - GD: 83.01) Tolerated (score: 0.11) Polymorphism (p-value: 1)
exon 8 c.1280T>C r.(1280u>c) p.(Met427Thr) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C45 (GV: 14.30 - GD: 81.04) Deleterious (score: 0.01) Disease causing (p-value: 0.551)
exon 8 c.1281G>T r.(1281g>u) p.(Met427Ile) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 14.30 - GD: 0.00) Tolerated (score: 0.05) Disease causing (prob: 0.944)
exon 8 c.1286A>G r.(1286a>g) p.(Gln429Arg) Substitution Substitution Substitution (missense) Unknown Likely benign Unknown Positive MAF is over 1% rs200294882 loss of cryptic splice acceptor protein is expressed Class C0 (GV: 129.65 - GD: 0.00) Tolerated (score: 0.72) Polymorphism (p-value: 1)
exon 8 c.1291_1299del r.(1291_1299del) p.(Leu431_Gln433del) Deletion Deletion Deletion Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing - in frame product protein is expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 10 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 8 c.1292_1295dup r.(1292_1295dup) p.(Gln433Alafs*74) duplication duplication Frameshift very severe Pathogenic Classic infantile Negative MAF is less than 1% rs996798292 no effect on splicing - causes an out of frame product protein is not expressed
exon 8 c.1293_1326+57del r.? p.? deletion deletion Frameshift very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported N.D. unknown
exon 8 c.1293_1312del r.(1293_1312del) p.(Gln433Aspfs*66) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 8 c.1297C>A r.(1297c>a) p.(Gln433Lys) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 57.03 - GD: 0.00) Tolerated (score: 0.87) Polymorphism (p-value: 1)
exon 8 c.1298A>C r.(1298a>c) p.(Gln433Pro) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 57.03 - GD: 65.86) Tolerated (score: 0.05) Polymorphism (prob: 1)
exon 8 c.1309C>T r.(1309c>u) p.(Arg437Cys) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Childhood Positive MAF is less than 1% rs770610356 no effect on splicing protein is expressed Class C15 (GV: 98.89 - GD: 126.72) Deleterious (score: 0.01) Disease causing (p-value: 0.998)
exon 8 c.1310G>A r.(1310g>a) p.(Arg437His) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs150868652 no effect on splicing protein is expressed Class C0 (GV: 98.89 - GD: 1.62) Deleterious (score: 0.05) Polymorphism (p-value: 0.957)
exon 8 c.1311_1312ins(26) r.spl p.? insertion insertion Frameshift very severe Pathogenic Classic infantile Unknown MAF not reported N.D. - causes an out of frame product unknown
exon 8 c.1316T>A r.(1316u>a) p.(Met439Lys) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Classic infantile Positive MAF is less than 1% rs747610090 no effect on splicing protein is expressed Class C35 (GV: 28.68 - GD: 90.65) Deleterious (score: 0.01) Disease causing (p-value: 0.978)
exon 8 c.1320_1322del r.(1320_1322del) p.(Met440del) deletion deletion deletion Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - causes an in frame product protein is expressed
exon 8 c.1322_1326+9del r.spl p.? Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported loss of exon 8 splice donor - causes an out of frame product protein is not expressed
exon 8 c.1324G>A r.(1324g>a) p.(Val442Met) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs377559348 no effect on splicing protein is expressed Class C0 (GV: 30.92 - GD: 0.00) Deleterious (score: 0.02) Disease causing (p-value: 0.721)
intron 8 c.1326+1G>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 8 splice donor unknown
intron 8 c.1326+5G>A r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) No category Unknown Uncertain significance Unknown Unknown MAF not reported weakens exon 8 splice donor unknown
intron 8 c.1326+132G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs894306 no effect on splicing protein is expressed
intron 8 c.1326+459C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs74679377 no effect on splicing protein is expressed
intron 8 c.1326+460G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12150323 no effect on splicing protein is expressed
intron 8 c.1327-514G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs72850826 no effect on splicing protein is expressed
intron 8 c.1327-356G>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs6565640 no effect on splicing protein is expressed
intron 8 c.1327-321del r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs140385114 no effect on splicing protein is expressed
intron 8 c.1327-269A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs6565641 no effect on splicing protein is expressed
intron 8 c.1327-209C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs76604157 no effect on splicing protein is expressed
intron 8 c.1327-179G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2278620 no effect on splicing protein is expressed
intron 8 c.1327-118A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs74003628 no effect on splicing protein is expressed
intron 8 c.1327-54_1437+178del r.1327_1437del p.? deletion deletion deletion very severe Pathogenic Classic infantile Positive MAF not reported causes an in frame skip of exon 9 causes an in frame product protein is expressed
intron 8 c.1327-18A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2278619 no effect on splicing protein is expressed
intron 8 c.1327-2A>G r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 9 splice acceptor unknown
intron 8 c.1327-2A>C r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 9 splice acceptor unknown
exon 9 c.1331C>G r.(1331c>g) p.(Pro444Arg) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 102.71) Deleterious (score: 0) Disease causing (p-value: 1)
exon 9 c.1333G>C r.(1333g>c) p.(Ala445Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Childhood Positive MAF not reported decreased enzymatic activity in expression study no effect on splicing protein is expressed Class C0 (GV: 113.34 - GD: 1.62) Tolerated (score: 0.21) Disease causing (p-value: 0.863)
exon 9 c.1354_1372del r.(1354_1372del) p.(Ala452Thrfs*19) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 9 c.1356del r.(1356del) p.(Ser454Alafs*23) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 9 c.1358_1361del r.(1358_1361del) p.(Gly453Alafs*23) Deletion Deletion Frameshift very severe Pathogenic Classic infantile Unknown MAF not reported generates a new cryptic splice acceptor site unknown
exon 9 c.1364A>C r.(1364a>c) p.(Tyr455Cys) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Childhood Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 143.11) Deleterious (score: 0) Disease causing (p-value: 0.98)
exon 9 c.1364A>T r.(1364a>u) p.(Tyr455Phe) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 21.61) Deleterious (score: 0) Disease causing (p-value: 0.794)
exon 9 c.1370C>T r.(1370c>u) p.(Pro457Leu) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Childhood Positive MAF not reported gives 10% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 95.38 - GD: 4.86) Tolerated (score: 0.83) Disease causing (p-value: 1)
exon 9 c.1370C>A r.(1370c>a) p.(Pro457His) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 95.38 - GD: 40.97) Deleterious (score: 0.05) Disease causing (p-value: 1)
exon 9 c.1371del r.(1371del) p.(Tyr458Thrfs*19) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 9 c.1373A>G r.(1373a>g) p.(Tyr458Cys) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Unknown Positive MAF not reported 45% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 157.49 - GD: 91.34) Deleterious (score: 0.03) Disease causing (p-value: 0.854)
exon 9 c.1374C>T r.1374c>u p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800305 no effect on splicing protein is expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 11 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 9 c.1375G>A r.(1375g>a) p.(Asp459Asn) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs535644999 no effect on splicing protein is expressed Class C0 (GV: 44.60 - GD: 11.33) Deleterious (score: 0.02) Disease causing (p-value: 0.992)
exon 9 c.1377_1379del r.(1377_1379del) p.(Asp459del) Deletion Deletion Deletion Very severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 9 c.1378G>T r.(1378g>u) p.(Glu460*) substitution substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 9 c.1381G>A r.(1381g>a) p.(Gly461Ser) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 109.55 - GD: 46.81) Tolerated (score: 0.52) Disease causing (p-value: 1)
exon 9 c.1385T>C r.(1385u>c) p.(Leu462Pro) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 4.86 - GD: 95.38) Deleterious (score: 0) Disease causing (p-value: 1)
exon 9 c.1388_1406del r.(1388_1406del) p.(Arg463Profs*8) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 9 c.1396del r.(1396del) p.(Val466Phefs*11) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 9 c.1396dup r.(1396dup) p.(Val466Glyfs*40) duplication duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs1273392818 no effect on splicing - causes an out of frame product protein is not expressed
exon 9 c.1396G>T r.(1396g>u) p.(Val466Phe) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C45 (GV: 0.00 - GD: 48.95) Deleterious (score: 0) Disease causing (p-value: 1)
exon 9 c.1397T>G r.(1397u>g) p.(Val466Gly) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Childhood Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 109.55) Deleterious (score: 0) Disease causing (p-value: 1)
exon 9 c.1402A>T r.(1402a>u) p.(Ile468Phe) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs886043148 no effect on splicing protein is expressed Class C0 (GV: 28.68 - GD: 21.28) Deleterious (score: 0.01) Disease causing (prob: 0.999)
exon 9 c.1408_1410del r.(1408_1410del) p.(Asn470del) Deletion Deletion Deletion Unknown Likely pathogenic Classic infantile Positive MAF is less than 1% rs748893499 no effect on splicing - in frame product protein is expressed
exon 9 c.1409A>G r.(1409a>g) p.(Asn470Ser) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported generates a new cryptic splice acceptor site unknown Class C15 (GV: 23.01 - GD: 44.87) Deleterious (score: 0.04) Disease causing (prob: 0.987)
exon 9 c.1409A>C r.(1409a>c) p.(Asn470Thr) Substitution Substitution Substitution (missense) unknown Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs144155165 no effect on splicing protein is expressed Class C25 (GV: 23.01 - GD: 64.77) Deleterious (score: 0.02) Disease causing (prob: 0.996)
exon 9 c.1411_1414del r.(1411_1414del) p.(Glu471Profs*5) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs770276275 no effect on splicing - causes an out of frame product protein is not expressed
exon 9 c.1431del r.(1431del) p.(Ile477Metfs*43) deletion deletion Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 9 c.1432G>A r.(1432g>a) p.(Gly478Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs778068209 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 1)
exon 9 c.1437G>C r.[(1437g>c), r.(spl?)] p.[(Lys479Asn), p.(?)] Substitution Substitution/ Splicing (splice donor site) Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Unknown MAF not reported weakens exon 9 splice donor unknown Class C25 (GV: 32.40 - GD: 65.72) Tolerated (score: 0.06) Disease causing (p-value: 0.998)
exon 9 c.1437G>A r.[1437g>a, 1327_1437del] p.[(=), (Asp443_Lys479del)] Substitution Substitution/ Splicing (splice donor site) Substitution (silent) Less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported gives 1,2% residual activity in expression study - causes exon 9 skip weakens exon 9 splice donor detection of leaky wildtype splicing unknown Class C25 (GV: 32.40 - GD: 65.72) Tolerated (score: 0.06) Disease causing (p-value: 0.998)
intron 9 c.1437+1G>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile or Childhood Unknown MAF not reported loss of exon 9 splice donor unknown
intron 9 c.1437+2T>C r.1327_1437del p.(Asp443_Lys479del) Substitution Substitution/ Splicing (splice donor site) Deletion Very severe Pathogenic Classic infantile Unknown MAF not reported causes skip of exon 9 loss of exon 9 splice donor unknown
intron 9 c.1438-220A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2278618 no effect on splicing protein is expressed
intron 9 c.1438-108G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12944802 no effect on splicing protein is expressed
intron 9 c.1437+4G>C r.(spl?) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 9 c.1438-19G>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304844 no effect on splicing protein is expressed
intron 9 c.1438-2A>G r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 10 splice acceptor unknown
intron 9 c.1438-1G>C r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 10 splice acceptor unknown
intron 9 c.1438-1G>T r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Uncertain significance Unknown Unknown MAF is less than 1% rs147804176 loss of exon 10 splice acceptor unknown
exon 10 c.1441del r.(1441del) p.(Trp481Glyfs*39) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 10 c.1441T>C r.(1441u>c) p.(Trp481Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs772883420 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 101.29) Deleterious (score: 0) Disease causing (p-value: 1)
exon 10 c.1442G>A r.(1442g>a) p.(Trp481*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no protein on western blot no effect on splicing no endogeneous protein on western blot protein is not expressed
exon 10 c.1445C>T r.(1445c>u) p.(Pro482Leu) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (p-value: 1)
exon 10 c.1445C>G r.(1445c>g) p.(Pro482Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported 0% residual activity in and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 102.71) Deleterious (score: 0) Disease causing (p-value: 1)
exon 10 c.1446del r.(1446del) p.(Ser484Profs*36) Substitution Substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 10 c.1447G>A r.(1447g>a) p.(Gly483Arg) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs770590394 0% residual activity and affects secretion in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 0.999)
exon 10 c.1447G>T r.(1447g>u) p.(Gly483Trp) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 183.79) Deleterious (score: 0) Disease causing (prob: 0.999)
exon 10 c.1448G>T r.(1448g>u) p.(Gly483Val) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 109.55) Deleterious (score: 0) Disease causing (p-value: 1)
exon 10 c.1456G>C r.(1456g>c) p.(Ala486Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 93.66 - GD: 26.78) Tolerated (score: 0.07) Disease causing (p-value: 0.977)
exon 10 c.1456G>T r.(1456g>u) p.(Ala486Ser) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs1283045273 no effect on splicing protein is expressed Class C15 (GV: 93.66 - GD: 99.13) Tolerated (score: 0.06) Disease causing (prob: 0.841)
exon 10 c.1456_1468del r.(1456_1468del) p.(Ala486Serfs*30) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 12 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 10 c.1460T>C r.(1460u>c) p.(Phe487Ser) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing endogenous protein on western blot protein is expressed Class C35 (GV: 39.66 - GD: 147.97) Deleterious (score: 0) Disease causing (p-value: 0.997)
exon 10 c.1464dup r.1464dup p.(Asp489Argfs*17) Duplication Duplication Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 10 c.1465G>A r.(1465g>a) p.(Asp489Asn) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs398123169 decreased enzymatic activity in expression study no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 23.01) Deleterious (score: 0) Disease causing (p-value: 1)
exon 10 c.1465G>T r.(1465g>u) p.(Asp489Tyr) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 159.94) Deleterious (score: 0) Disease causing (p-value: 1)
exon 10 c.1466A>G r.(1466a>g) p.(Asp489Gly) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 93.77) Deleterious (score: 0) Disease causing (p-value: 1)
exon 10 c.1468T>C r.(1468u>c) p.(Phe490Leu) Substitution Substitution Substitution (missense) Less severe Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 102.86 - GD: 4.86) Tolerated (score: 0.15) Disease causing (p-value: 1)
exon 10 c.1470C>A r.(1470c>a) p.(Phe490Leu) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Childhood Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 102.86 - GD: 4.86) Tolerated (score: 0.15) Disease causing (prob: 0.994)
exon 10 c.1477C>T r.(1477c>u) p.(Pro493Ser) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 102.71 - GD: 70.74) Deleterious (score: 0.03) Disease causing (prob: 0.997)
exon 10 c.1478C>T r.(1478c>u) p.(Pro493Leu) Substitution Substitution Substitution (missense) Unknown Uncertain significance Adult Positive MAF is less than 1% rs148842275 no effect on splicing protein is expressed Class C0 (GV: 102.71 - GD: 55.05) Deleterious (score: 0.02) Disease causing (p-value: 1)
exon 10 c.1493G>A r.(1493g>a) p.(Trp498*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Classic infantile Unknown MAF not reported loss of a cryptic splice donor site unknown
exon 10 c.1495T>A r.(1495u>a) p.(Trp499Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported weakens a cryptic splice donor site protein is expressed Class C65 (GV: 0.00 - GD: 101.29) Deleterious (score: 0) Disease causing (p-value: 1)
exon 10 c.1496G>A r.(1496g>a) p.(Trp499*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs766680292 no protein on western blot strengthens a cryptic splice donor site no endogeneous protein on western blot protein is not expressed
exon 10 c.1497G>A r.(1497g>a) p.(Trp499*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot strengthens a cryptic splice donor site no endogeneous protein on western blot protein is not expressed
exon 10 c.1501_1515del r.(1501_1515del) p.(Asp501_Glu505del) Deletion Deletion Deletion potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed
exon 10 c.1504A>G r.(1504a>g) p.(Met502Val) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs376067362 no effect on splicing protein is expressed Class C0 (GV: 222.05 - GD: 3.24) Tolerated (score: 0.26) Polymorphism (p-value: 0.804)
exon 10 c.1507del r.(1507del) p.(Val503Trpfs*17) Deletion Deletion Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 10 c.1509_1511del r.(1509_1511del) p.(Ala504del) Deletion Deletion Deletion Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 10 c.1526A>T r.(1526a>u) p.(Gln509Leu) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported strengthens a cryptic splice donor site unknown Class C0 (GV: 239.06 - GD: 90.63) Deleterious (score: 0.02) Disease causing (prob: 0.986)
exon 10 c.1531C>A r.(1531c>a) p.(Pro511Thr) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported strengthens a cryptic splice donor site unknown Class C35 (GV: 0.00 - GD: 37.56) Deleterious (score: 0) Disease causing (prob: 1)
exon 10 c.1537G>A r.(1537g>a) p.(Asp513Asn) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs748047271 no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 23.01) Deleterious (score: 0) Disease causing (prob: 1)
exon 10 c.1538A>G r.(1538a>g) p.(Asp513Gly) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual enzyme activity and affects processing & secretion of GAA no effect on splicing protein found on western blot protein is expressed Class C65 (GV: 0.00 - GD: 93.77) Deleterious (score: 0) Disease causing (prob: 1)
exon 10 c.1540G>C r.(1540g>c) p.(Gly514Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 137.69 - GD: 27.62) Tolerated (score: 0.17) Disease causing (p-value: 1)
exon 10 c.1544T>A r.(1544u>a) p.(Met515Lys) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 92.35 - GD: 44.44) Deleterious (score: 0.02) Disease causing (p-value: 0.997)
exon 10 c.1548G>A r.(1548g>a) p.(Trp516*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs140826989 no protein on western blot no effect on splicing no endogeneous protein on western blot protein is not expressed
intron 10 c.1551+1G>C r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 10 splice donor unknown
intron 10 c.1551+1G>T r.[=,1438_1551del] p.[(=),(Val480_Ile517del)] Substitution Substitution/ Splicing (splice donor site) Deletion Potentially less severe Pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs770780848 causes skip of exon 10 loss of exon 10 splice donor detection of leaky wildtype splicing unknown
intron 10 c.1551+1G>A r.[=,1438_1551del] p.[(=),(Val480_Ile517del)] Substitution Substitution/ Splicing (splice donor site) Deletion Very severe Pathogenic Unknown (disease-associated) Positive MAF not reported causes skip of exon 10 loss of exon 10 splice donor detection of leaky wildtype splicing unknown
intron 10 c.1551+2T>G r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 10 splice donor unknown
intron 10 c.1551+3_1551+6del r.(spl?) p.? Deletion Deletion/ Splicing (intron variant) No category Potentially less severe Uncertain significance Unknown (disease-associated) Unknown MAF not reported loss of exon 10 splice donor unknown
intron 10 c.1551+3A>T r.(spl?) p.? Substitution Substitution/ Splicing (splice donor site) No category potentially less severe Unknown significance Unknown (disease-associated) Unknown MAF not reported weakens exon 10 splice donor site unknown
intron 10 c.1551+5G>A r.(spl?) p.? substitution Substitution/ Splicing (intron variant) No category very severe Unknown significance Unknown (disease-associated) Unknown MAF not reported loss of exon 9 splice donor site unknown
intron 10 c.1551+42G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is over 1% rs115427918 no effect on splicing protein is expressed
intron 10 c.1551+49C>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304843 no effect on splicing protein is expressed
intron 10 c.1551+49C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 10 c.1552-3C>G r.[=,1551ins30, 1551ins100] p.[(=), (Val480_Ile517del), (Ile517_Asp518insSerHisLeuProAlaAlaLeuLeuLeuGln)] Substitution Substitution/ Splicing (intron variant) Deletion/ Insertion Potentially mild Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs375470378 full and partial exon 10 skip and intron 10 inclusion weakens exon 11 splice acceptor detection of leaky wildtype splicing unknown
exon 11 c.1555A>G r.(1555a>g) p.(Met519Val) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 20.52) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1556T>C r.(1556u>c) p.(Met519Thr) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 81.04) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1559A>G r.(1559a>g) p.(Asn520Ser) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C45 (GV: 0.00 - GD: 46.24) Deleterious (score: 0) Disease causing (prob: 1)
exon 11 c.1560C>G r.(1560c>g) p.(Asn520Lys) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 93.88) Deleterious (score: 0) Disease causing (prob: 0.886)
exon 11 c.1561G>C r.(1561g>c) p.(Glu521Gln) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C25 (GV: 0.00 - GD: 29.27) Deleterious (score: 0) Disease causing (p-value: 1)

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 13 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 11 c.1561G>A r.(1561g>a) p.(Glu521Lys) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile or Childhood Positive MAF is less than 1% rs121907937 no effect on splicing protein is expressed Class C55 (GV: 0.00 - GD: 56.87) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1562A>T r.(1562a>u) p.(Glu521Val) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Classic infantile Unknown MAF not reported new weak cryptic splice donor unknown Class C65 (GV: 0.00 - GD: 121.34) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1564C>G r.(1564c>g) p.(Pro522Ala) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported gives 0% residual activity in expression study no effect on splicing protein is expressed Class C25 (GV: 0.00 - GD: 26.87) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1564C>A r.(1564c>a) p.(Pro522Thr) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 0.00 - GD: 37.56) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1564C>T r.(1564c>u) p.(Pro522Ser) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0,8% residual activity in expression study and affects secretion & processing in ... no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 73.35) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1568C>A r.(1568c>a) p.(Ser523Tyr) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects processing in expression study no effect on splicing protein is expressed Class C15 (GV: 99.13 - GD: 109.77) Deleterious (score: 0) Disease causing (p-value: 0.988)
exon 11 c.1574T>A r.(1574u>a) p.(Phe525Tyr) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Unknown (found only in NBS) Positive MAF not reported gives 13,4% residual activity in expression study no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 21.61) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1579_1580del r.(1579_1580del) p.(Arg527Glyfs*3) Deletion Deletion Frameshift very severe Pathogenic Classic infantile Unknown MAF is less than 1% rs1291214871 loss of cryptic splice acceptor site unknown
exon 11 c.1581G>A r.1581g>a p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1042396 no effect on splicing protein is expressed
exon 11 c.1582_1583del r.(1582_1583del) p.(Gly528Leufs*2) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 11 c.1583G>C r.(1583g>c) p.(Gly528Ala) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported rs794727016 no effect on splicing protein is expressed Class C55 (GV: 0.00 - GD: 60.00) Deleterious (score: 0) Disease causing (prob: 1)
exon 11 c.1585_1586delinsGT r.(1585_1586delinsGU) p.(Ser529Val) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Adult Positive MAF not reported no effect on splicing protein is expressed
exon 11 c.1591dup r.(1591dup) p.(Asp531Glyfs*7) Duplication Duplication Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 11 c.1594G>A r.(1594g>a) p.(Gly532Ser) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Adult Positive MAF is less than 1% rs773576381 no effect on splicing protein is expressed Class C0 (GV: 59.16 - GD: 46.81) Tolerated (score: 0.14) Disease causing (prob: 1)
exon 11 c.1597T>G r.(1597u>g) p.(Cys533Gly) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity in GAA expression construct no effect on splicing protein is expressed Class C0 (GV: 195.00 - GD: 31.89) Deleterious (score: 0.05) Disease causing (prob: 1)
exon 11 c.1602_1605delinsAGG r.(1602_1605delinsagg) p.(Asn535Glyfs*43) Deletion/ insertion Deletion/ insertion Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 11 c.1610del r.(1610del) p.(Glu537Glyfs*41) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs762060817 no effect on splicing - causes an out of frame product protein is expressed
exon 11 c.1626C>G r.(1626c>g) p.(=) Substitution Substitution/ Splicing (splice donor site) Substitution (silent) Unknown Uncertain significance Unknown (disease-associated) Unknown MAF not reported new cryptic splice donor unknown
exon 11 c.1627T>G r.(1627u>g) p.(Tyr543Asp) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 247.85 - GD: 110.05) Deleterious (score: 0) Disease causing (prob: 1)
exon 11 c.1629C>G r.(1629c>g) p.(Tyr543*) substitution substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported new cryptic splice donor site unknown
exon 11 c.1634C>T r.(1634c>u) p.(Pro545Leu) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Childhood or Adult Unknown MAF is less than 1% rs121907942 weakens exon 11 splice donor unknown Class C0 (GV: 208.63 - GD: 94.04) Deleterious (score: 0) Disease causing (p-value: 1)
exon 11 c.1636G>C r.(1636g>c) p.(Gly546Arg) Substitution Substitution/ Splicing (splice donor site) Substitution (missense) Very severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported loss of splice donor site unknown Class C0 (GV: 208.58 - GD: 95.56) Deleterious (score: 0.01) Disease causing (prob: 1)
intron 11 c.1636+1G>C r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 11 splice donor unknown
intron 11 c.1636+5G>T r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) No category Potentially mild Likely pathogenic Unknown (disease-associated) Unknown MAF not reported gives 13,7% residual activity in expression study weakens exon 11 splice donor unknown
intron 11 c.1636+5G>A r.(spl?) p.? substitution Substitution/ Splicing (intron variant) No category very severe Unknown significance Classic infantile Unknown MAF not reported loss of exon 10 splice donor site unknown
intron 11 c.1636+5G>C r.(1636_1637ins957 p.(Gly546fs*145) Substitution insertion/ Splicing (intron variant) Frameshift Very severe Pathogenic Classic infantile Unknown MAF not reported causes retention of intron 11 weakens exon 11 splice donor unknown
intron 11 c.1636+43G>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304842 generates a new cryptic splice accepter site unknown
intron 11 c.1636+117del r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs199788201 no effect on splicing protein is expressed
intron 11 c.1636+117C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12945868 no effect on splicing protein is expressed
intron 11 c.1636+118G>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889817 no effect on splicing protein is expressed
intron 11 c.1636+205C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs79673008 no effect on splicing protein is expressed
intron 11 c.1636+210G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs79487884 no effect on splicing protein is expressed
intron 11 c.1636+269C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs111625854 no effect on splicing protein is expressed
intron 11 c.1636+284G>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs111551014 no effect on splicing protein is expressed
intron 11 c.1636+389C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs7221675 no effect on splicing protein is expressed
intron 11 c.1636+390A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs7209921 no effect on splicing protein is expressed
intron 11 c.1636+404A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889818 no effect on splicing protein is expressed
intron 11 c.1637-185A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12951255 no effect on splicing protein is expressed
intron 11 c.1637-2A>G r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 11 splice acceptor unknown
exon 12 c.1642G>T r.(1642g>u) p.(Val548Phe) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 234.99 - GD: 21.28) Deleterious (score: 0.01) Disease causing (p-value: 0.57)

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 14 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 12 c.1645G>A r.(1645g>a) p.(Gly549Arg) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Unknown (disease-associated) Unknown MAF not reported new cryptic splice donor unknown Class C15 (GV: 206.04 - GD: 124.98) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1645G>C r.(1645g>c) p.(Gly549Arg) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 206.04 - GD: 124.98) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1650dup r.(1650dup) p.(Thr551Aspfs*85) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs766398206 no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 12 c.1650del r.(1650del) p.(Thr551Profs*27) deletion deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% no effect on splicing - causes an out of frame product protein is not expressed
exon 12 c.1654del r.(1654del) p.(Leu552Serfs*26) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 12 c.1655T>C r.(1655u>c) p.(Leu552Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs779556619 0% residual activity in GAA expression construct no effect on splicing protein is expressed Class C0 (GV: 234.72 - GD: 50.17) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1657C>T r.(1657c>u) p.(Gln553*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 12 c.1666A>G r.(1666a>g) p.(Thr556Ala) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 215.09 - GD: 8.09) Deleterious (score: 0) Disease causing (p-value: 0.999)
exon 12 c.1669A>T r.(1669a>u) p.(Ile557Phe) Substitution Substitution Substitution (missense) Very severe Likely pathogenic Classic infantile Positive MAF not reported 2.9% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 234.77 - GD: 21.28) Deleterious (score: 0.03) Disease causing (p-value: 0.909)
exon 12 c.1670T>G r.(1670u>g) p.(Ile557Ser) substitution substitution Substitution (nonsense) very severe Pathogenic Unknown Unknown MAF not reported generates a new cryptic splice accepter site unknown Class C0 (GV: 234.77 - GD: 64.73) Deleterious (score: 0.01) Disease causing (prob: 0.961)
exon 12 c.1672T>A r.(1672u>a) p.(Cys558Ser) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 4,8% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 213.42 - GD: 59.88) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1673G>C r.(1673g>c) p.(Cys558Ser) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 2,1% residual activity and affects secretion & processing in expression study weakens a cryptic splice acceptor site protein is expressed Class C0 (GV: 213.42 - GD: 59.88) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1681_1699dup r.(1681_1699dup) p.(Thr567Lysfs*75) Duplication Duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 12 c.1687C>T r.(1687c>u) p.(Gln563*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing no endogeneous protein on western blot protein is not expressed
exon 12 c.1688A>T r.(1688a>u) p.(Gln563Leu) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C25 (GV: 45.75 - GD: 112.44) Deleterious (score: 0.02) Disease causing (prob: 1)
exon 12 c.1694_1697del r.(1694_1697del) p.(Leu565Profs*12) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 12 c.1696T>C r.(1696u>c) p.(Ser566Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 79.79 - GD: 41.25) Deleterious (score: 0.03) Disease causing (p-value: 1)
exon 12 c.1703A>T r.(1703a>u) p.(His568Leu) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 28.82 - GD: 97.52) Deleterious (score: 0.03) Disease causing (p-value: 1)
exon 12 c.1704C>G r.(1704c>g) p.(His568Gln) Substitution Substitution Substitution (missense) Unknown Likely pathogenic Adult Unknown MAF not reported new cryptic splice acceptor unknown Class C0 (GV: 28.82 - GD: 19.90) Tolerated (score: 0.07) Disease causing (p-value: 0.927)
exon 12 c.1705dup r.(1705dup) p.(tyr569Leufs*67) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 12 c.1710C>G r.(1710c>g) p.(Asn570Lys) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0,9% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C25 (GV: 46.24 - GD: 93.76) Deleterious (score: 0.02) Disease causing (p-value: 0.964)
exon 12 c.1716C>G r.(1716c>g) p.(His572Gln) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Unknown MAF not reported 0% residual activity and affects secretion & processing in expression study new cryptic splice acceptor unknown Class C15 (GV: 0.00 - GD: 24.08) Deleterious (score: 0) Disease causing (p-value: 0.978)
exon 12 c.1716C>A r.(1716c>a) p.(His572Gln) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs772962666 no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 24.08) Deleterious (score: 0) Disease causing (prob: 0.977)
exon 12 c.1717A>C r.(1717a>c) p.(Asn573His) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 68.35) Deleterious (score: 0) Disease causing (p-value: 0.992)
exon 12 c.1719C>A r.(1719c>a) p.(Asn573Lys) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 93.88) Deleterious (score: 0) Polymorphism (p-value: 0.637)
exon 12 c.1721T>C r.(1721u>c) p.(Leu574Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C45 (GV: 14.30 - GD: 86.59) Deleterious (score: 0.01) Disease causing (prob: 1)
exon 12 c.1724A>C r.(1724a>c) p.(Tyr575Ser) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 143.11) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1724A>G r.(1724a>g) p.(Tyr575Cys) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 2% residual activity and affects processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 193.72) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1725C>A r.(1725c>a) p.(Tyr575*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs112517802 new cryptic splice acceptor protein is not expressed
exon 12 c.1726G>A r.1726g>a p.(Gly576Ser) Substitution Substitution Substitution (missense) Presumably non-pathogenic Benign Unknown Unknown MAF is over 5% rs1800307 new cryptic splice acceptor - (frequent background in Asian population) unknown Class C55 (GV: 0.00 - GD: 55.27) Deleterious (score: 0) Polymorphism (p-value: 0)
exon 12 c.1726G>C r.(1726g>c) p.(Gly576Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 3,8% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1727G>A r.(1727g>a) p.(Gly576Asp) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 93.77) Deleterious (score: 0) Disease causing (p-value: 1)
exon 12 c.1735G>A r.(1735g>a) p.(Glu579Lys) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 121.34 - GD: 34.45) Tolerated (score: 0.16) Disease causing (p-value: 1)
exon 12 c.1748C>T r.(1748c>u) p.(Ser583Phe) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C25 (GV: 57.75 - GD: 102.86) Deleterious (score: 0) Disease causing (p-value: 0.997)
exon 12 c.1753_2799del r.(1753_2799del) p.(Arg586_Lys933del) deletion Deletion/ Splicing deletion very severe Likely pathogenic Classic infantile Unknown MAF not reported causes an in frame product unknown
exon 12 c.1754G>T r.[(1754g>u), r.(spl?)] p.[(Arg585Met), p.?] Substitution Substitution/ Splicing (splice donor site) Substitution (missense) Less severe Uncertain significance Unknown (disease-associated) Unknown MAF not reported loss of cryptic splice acceptor unknown Class C0 (GV: 173.88 - GD: 15.94) Tolerated (score: 0.1) Disease causing (p-value: 1)
exon 12 c.1754G>A r.[(1754g>a), r.(spl?)] p.[(Arg585Lys), p.?] Substitution Substitution/ Splicing (splice donor site) Substitution (missense) Less severe Uncertain significance Childhood or Adult Unknown MAF is less than 1% rs747373179 gives 94% residual activity in expression study loss of cryptic splice acceptor unknown Class C0 (GV: 173.88 - GD: 0.00) Tolerated (score: 0.56) Disease causing (p-value: 0.997)
intron 12 c.1754+1G>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot loss of exon 12 splice donor no endogeneous protein on western blot unknown
intron 12 c.1754+1dup r.spl p.? duplication duplication/ Splicing (splice donor site) No category very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of splice donor site and generation of a new cryptic splice donor site unknown
intron 12 c.1754+2T>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no protein on western blot loss of exon 12 splice donor no endogeneous protein on western blot unknown

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 15 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
intron 12 c.1754+2T>C r.spl p.? Substitution Substitution (splice donor site) No category very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported weakens splice donor site unknown
intron 12 c.1754+12G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304840 no effect on splicing protein is expressed
intron 12 c.1754+100C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs113688685 no effect on splicing protein is expressed
intron 12 c.1754+104C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304839 no effect on splicing protein is expressed
intron 12 c.1754+144C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304838 no effect on splicing protein is expressed
intron 12 c.1755-186A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs62075593 no effect on splicing protein is expressed
intron 12 c.1754+16C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
intron 12 c.1755-1G>A r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 13 splice acceptor unknown
exon 13 c.1760T>C r.(1760u>c) p.(Leu587Pro) Substitution Substitution Substitution (missense) Unknown Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 4.86 - GD: 95.38) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1771C>T r.(1771c>u) p.(Arg591Trp) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs770983413 no effect on splicing protein is expressed Class C0 (GV: 170.08 - GD: 46.61) Deleterious (score: 0.01) Polymorphism (p-value: 1)
exon 13 c.1776del r.(1776del) p.(Thr593Hisfs*5) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 13 c.1780C>T r.(1780c>u) p.(Arg594Cys) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported rs1428112902 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 179.53) Deleterious (score: 0) Disease causing (prob: 1)
exon 13 c.1781G>C r.(1781g>c) p.(Arg594Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Childhood or adult Positive MAF is less than 1% rs775450536 1,2% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 102.71) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1781G>A r.(1781g>a) p.(Arg594His) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Childhood Positive MAF is less than 1% rs775450536 0,1% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C25 (GV: 0.00 - GD: 28.82) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1784C>T r.(1784c>u) p.(Pro595Leu) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs763772240 no effect on splicing no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (prob: 1)
exon 13 c.1796C>A r.(1796c>a) p.(Ser599Tyr) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs753505203 gives 0% residual activity in expression study no effect on splicing protein is expressed Class C15 (GV: 57.75 - GD: 92.25) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1796C>T r.(1796c>u) p.(Ser599Phe) Substitution Substitution Substitution (missense) Less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C25 (GV: 57.75 - GD: 102.86) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1798C>T r.(1798c>u) p.(Arg600Cys) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity in GAA expression construct no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 179.53) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1799G>A r.(1799g>a) p.(Arg600His) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs377544304 no effect on splicing protein is expressed Class C25 (GV: 0.00 - GD: 28.82) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1799G>C r.(1799g>c) p.(Arg600Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported rs377544304 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 102.71) Deleterious (score: 0) Disease causing (prob: 1)
exon 13 c.1799G>T r.(1799g>u) p.(Arg600Leu) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 101.88) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1802C>A r.(1802c>a) p.(Ser601*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported new cryptic splice acceptor protein is not expressed
exon 13 c.1802C>G r.(1802c>g) p.(Ser601Trp) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C25 (GV: 99.13 - GD: 146.49) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1802C>T r.(1802c>u) p.(Ser601Leu) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0,4% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C15 (GV: 99.13 - GD: 95.33) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 13 c.1804A>G r.(1804a>g) p.(Thr602Ala) Substitution Substitution Substitution (missense) Less severe Uncertain significance Unknown Positive MAF is less than 1% rs781484283 5,8% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 154.81 - GD: 1.01) Tolerated (score: 0.24) Polymorphism (p-value: 0.551)
exon 13 c.1805C>T r.(1805c>u) p.(Thr602Ile) substitution substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (found only in NBS) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 154.81 - GD: 0.00) Tolerated (score: 0.08) Disease causing (prob: 0.895)
exon 13 c.1814G>A r.(1814g>a) p.(Gly605Asp) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 55.27 - GD: 65.41) Deleterious (score: 0.02) Disease causing (p-value: 1)
exon 13 c.1819_1836del r.(1819_1836del) p.(Gly607_His612del) Deletion Deletion Deletion Very severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 13 c.1820G>A r.(1820g>a) p.(Gly607Asp) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 87.17 - GD: 52.62) Tolerated (score: 0.12) Disease causing (p-value: 1)
exon 13 c.1822C>T r.(1822c>u) p.(Arg608*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing no endogeneous protein on western blot protein is not expressed
exon 13 c.1822del r.(1822del) p.(Arg608Aspfs*88) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 13 c.1824_1828dup r.(1824_1828dup) p.(Ala610Aspfs*88) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% no effect on splicing - causes an out of frame product protein is not expressed
exon 13 c.1825T>G r.(1825u>g) p.(Tyr609Asp) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 105.73 - GD: 85.08) Deleterious (score: 0.02) Disease causing (prob: 0.964)
exon 13 c.1826dup r.(1826dup) p.(Tyr609*) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs754952153 no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 13 c.1827del r.(1827del) p.(Tyr609*) Deletion Deletion Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs781088002 no protein on western blot no effect on splicing no endogeneous protein on western blot protein is not expressed
exon 13 c.1827C>G r.(1827c>g) p.(Tyr609*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% new weak cryptic splice acceptor protein is not expressed
exon 13 c.1829C>T r.(1829c>u) p.(Ala610Val) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Childhood Positive MAF not reported 5% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 99.13 - GD: 64.43) Deleterious (score: 0.02) Polymorphism (p-value: 0.873)
exon 13 c.1830C>T r.(1830c>u) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
exon 13 c.1832G>A r.(1832g>a) p.(Gly611Asp) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 60.00 - GD: 81.64) Deleterious (score: 0.01) Disease causing (p-value: 0.968)
exon 13 c.1833_1847delinsACGGGGTAT c.(1833_1847delinsacgggguau) p.(His612_Asp616delinsArgGlyIle) Deletion/ insertion Deletion/ insertion Deletion/ Insertion Very severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - causes an in frame product protein is expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 16 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 13 c.1834C>T r.(1834c>u) p.(His612Tyr) Substitution Deletion/ insertion Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 94.54 - GD: 40.53) Tolerated (score: 0.31) Disease causing (p-value: 0.973)
exon 13 c.1835A>C r.(1835a>c) p.(His612Pro) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 94.54 - GD: 28.88) Tolerated (score: 0.22) Disease causing (prob: 0.991)
exon 13 c.1835A>G r.(1835a>g) p.(His612Arg) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs760546238 no effect on splicing protein is expressed Class C0 (GV: 94.54 - GD: 28.42) Tolerated (score: 0.28) Disease causing (prob: 0.961)
exon 13 c.1836C>G r.(1836c>g) p.(His612Gln) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported decreased enzymatic activity in expression study no effect on splicing protein is expressed Class C0 (GV: 94.54 - GD: 12.47) Tolerated (score: 0.22) Disease causing (p-value: 0.982)
exon 13 c.1837T>G r.(1837u>g) p.(Trp613Gly) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 183.79) Deleterious (score: 0) Disease causing (prob: 1)
exon 13 c.1839G>C r.(1839g>c) p.(Trp613Cys) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 214.36) Deleterious (score: 0) Disease causing (prob: 1)
exon 13 c.1840A>G r.(1840a>g) p.(Thr614Ala) Substitution Substitution Substitution (missense) unknown Uncertain significance Unknown (found only in NBS) Positive MAF not reported no effect on splicing protein is expressed Class C55 (GV: 0.00 - GD: 58.02) Deleterious (score: 0) Disease causing (prob: 0.999)
exon 13 c.1841C>A r.(1841c>a) p.(Thr614Lys) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs369531647 1,7% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 77.74) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1843G>A r.(1843g>a) p.(Gly615Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs549029029 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1844_1846del r.(1844_1846del) p.(Gly615del) deletion deletion deletion Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% no effect on splicing - causes an in frame product protein is expressed
exon 13 c.1844G>T r.(1844g>u) p.(Gly615Val) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 109.55) Deleterious (score: 0) Disease causing (prob: 1)
exon 13 c.1844G>A r.(1844g>a) p.(Gly615Glu) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs1243515778 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.85) Deleterious (score: 0) Disease causing (prob: 1)
exon 13 c.1846G>A r.(1846g>a) p.(Asp616Asn) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 23.01) Deleterious (score: 0) Disease causing (p-value: 1)
exon 13 c.1847dup r.(1847dup) p.(Asp616Glufs*20) Duplication Duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs1475559733 no effect on splicing - causes an out of frame product protein is not expressed
exon 13 c.1848dup r.(1848dup) p.(Val617Argfs*19) Duplication Duplication Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 13 c.1850T>C r.(1850u>c) p.(Val617Ala) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Unknown Positive MAF not reported gives 65% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 133.10 - GD: 25.33) Tolerated (score: 0.32) Disease causing (p-value: 0.999)
exon 13 c.1856G>A r.(1856g>a) p.(Ser619Asn) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Childhood or Adult Positive MAF is less than 1% rs753269119 4-6% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 99.13 - GD: 45.82) Deleterious (score: 0.01) Disease causing (p-value: 0.99)
exon 13 c.1857C>G r.(1857c>g) p.(Ser619Arg) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Classic infantile or Childhood Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 99.13 - GD: 95.56) Deleterious (score: 0.01) Disease causing (p-value: 0.915)
exon 13 c.1859C>A r.(1859c>a) p.(Ser620Tyr) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C25 (GV: 66.42 - GD: 122.27) Tolerated (score: 0.06) Polymorphism (prob: 0.945)
exon 13 c.1872C>T r.(1872c>u) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
exon 13 c.1879T>C r.(1879u>c) p.(Ser627Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0,5% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 73.35) Deleterious (score: 0) Disease causing (p-value: 0.915)
exon 13 c.1879_1881del r.(1879_1881delucc) p.(Ser627del) Deletion Deletion Deletion potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - causes an in frame product protein is expressed
exon 13 c.1880C>T r.(1880c>u) p.(Ser627Phe) Substitution Substitution Substitution (missense) Unknown Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 154.81) Deleterious (score: 0) Disease causing (p-value: 0.994)
exon 13 c.1886C>T r.(1886c>u) p.(Pro629Leu) Substitution Substitution Substitution (missense) Presumably non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% gives 49% residual activity in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (p-value: 1)
intron 13 c.1888+1G>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs776325453 no protein on western blot loss of exon 14 splice acceptor no endogeneous protein on western blot unknown
intron 13 c.1888+2_1888+15del r.spl p.? deletion Deletion/ Splicing (splice donor site) No category very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 13 splice donor site unknown
intron 13 c.1888+21G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304837 no effect on splicing protein is expressed
intron 13 c.1889-27_2040+23del r.spl p.? Deletion Deletion Frameshift Very severe Uncertain significance Unknown Negative MAF not reported unknown - causes an out of frame product protein is not expressed
exon 14 c.1895T>C r.(1895u>c) p.(Leu632Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (prob: 1)
exon 14 c.1895T>G r.(1895u>g) p.(Leu632Arg) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity and affects processing & secretion of GAA no effect on splicing protein found on western blot protein is expressed Class C65 (GV: 0.00 - GD: 101.88) Deleterious (score: 0) Disease causing (prob: 1)
exon 14 c.1903A>G r.(1903a>g) p.(Asn635Asp) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 79.35 - GD: 22.92) Tolerated (score: 0.2) Polymorphism (prob: 0.97)
exon 14 c.1905C>A r.(1905c>a) p.(Asn635Lys) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C15 (GV: 79.35 - GD: 69.77) Tolerated (score: 0.06) Polymorphism (p-value: 0.811)
exon 14 c.1912G>T r.(1912g>u) p.(Gly638Trp) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Unknown MAF is less than 1% rs757617999 new cryptic splice donor unknown Class C65 (GV: 0.00 - GD: 183.79) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1913G>T r.(1913g>u) p.(Gly638Val) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 109.55) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1913G>A r.(1913g>a) p.(Gly638Glu) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Unknown MAF is less than 1% rs1294428728 generates a new cryptic splice donor site unknown Class C65 (GV: 0.00 - GD: 97.85) Deleterious (score: 0) Disease causing (prob: 1)
exon 14 c.1917G>A r.(1917g>a) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Unknown MAF not reported strengthens a cryptic splice donor site unknown
exon 14 c.1920T>G r.(1920u>g) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
exon 14 c.1921C>G r.(1921c>g) p.(Leu641Val) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 30.27 - GD: 20.52) Tolerated (score: 0.05) Polymorphism (p-value: 0.596)
exon 14 c.1923G>A r.(1923g>a) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Unknown MAF not reported new weak cryptic splice acceptor unknown
exon 14 c.1924G>T r.(1924g>u) p.(Val642Phe) Substitution Substitution Substitution (missense) Unknown Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 28.68 - GD: 21.28) Deleterious (score: 0.01) Disease causing (p-value: 1)

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 17 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 14 c.1925T>A r.(1925u>a) p.(Val642Asp) Substitution Substitution Substitution (missense) unknown Uncertain significance Unknown (found only in NBS) Positive MAF not reported no effect on splicing protein is expressed Class C45 (GV: 28.68 - GD: 152.22) Deleterious (score: 0) Disease causing (prob: 1)
exon 14 c.1927G>A r.[1927g>a, 1755_1928del, 1889_1928del] p.[Gly643Arg, Leu587_Ala644del, Glu630Gly*53] Substitution Substitution/ Splicing (exon variant) Substitution (missense) Potentially less severe Pathogenic Classic infantile Unknown MAF is less than 1% rs28937909 causes partial skipping of exon 14 new cryptic splice acceptor unknown Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1930_1936dup r.(1930_1936dup) p.(Val646Glyfs*93) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs748829376 no effect on splicing - causes an out of frame product protein is not expressed
exon 14 c.1930G>C r.(1930g>c) p.(Ala644Pro) Substitution Substitution Substitution (missense) Unknown Uncertain significance Adult Positive MAF not reported no effect on splicing protein is expressed Class C25 (GV: 0.00 - GD: 26.87) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1933G>C r.(1933g>c) p.(Asp645His) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF is less than 1% rs368438393 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 81.24) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1933G>A r.(1933g>a) p.(Asp645Asn) Substitution Substitution Substitution (missense) Potentially less severe Pathogenic Classic infantile Positive MAF is less than 1% rs368438393 <1% residual acitivty and affects processing in expression study no effect on splicing endogenous protein on western blot protein is expressed Class C15 (GV: 0.00 - GD: 23.01) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1933G>T r.(1933g>u) p.(Asp645Tyr) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 159.94) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1935C>A r.(1935c>a) p.(Asp645Glu) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs28940868 no effect on splicing endogenous protein on western blot protein is expressed Class C35 (GV: 0.00 - GD: 44.60) Deleterious (score: 0) Disease causing (p-value: 0.923)
exon 14 c.1941C>G r.(1941c>g) p.(Cys647Trp) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs776948121 no effect on splicing protein is expressed Class C15 (GV: 195.00 - GD: 116.53) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1942G>A r.(1942g>a) p.(Gly648Ser) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Unknown MAF is less than 1% rs536906561 new cryptic splice acceptor unknown Class C55 (GV: 0.00 - GD: 55.27) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1943G>A r.(1943g>a) p.(Gly648Asp) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 93.77) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1944_1950del r.(1944_1950del) p.(Phe649_Leu650del) Deletion Deletion Deletion potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing - causes an in frame product protein is expressed
exon 14 c.1951_1952delinsT r.(1951_1952delinsu) p.(Gly651Serfs*45) Deletion/ insertion Deletion/ insertion Frameshift Very severe Uncertain significance Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 14 c.1952dup r.(1951del) p.(Asn652Glnfs*85) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 14 c.1958C>A r.(1958c>a) p.(Thr653Asn) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs763456921 no effect on splicing protein is expressed Class C15 (GV: 58.27 - GD: 64.58) Tolerated (score: 0.11) Disease causing (p-value: 0.997)
exon 14 c.1960T>C r.(1960u>c) p.(Ser654Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 74.82 - GD: 24.03) Deleterious (score: 0.03) Polymorphism (p-value: 1)
exon 14 c.1961C>G r.(1961c>g) p.(Ser654*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 14 c.1962_1964del r.(1962_1964del) p.(Glu656del) Deletion Deletion Deletion Very severe Uncertain significance Unknown Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing - in frame product protein is expressed
exon 14 c.1971G>A r.(1971g>a) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 14 c.1978C>T r.(1978c>u) p.(Arg660Cys) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF is less than 1% rs759518659 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 179.53) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1979G>A r.(1979g>a) p.(Arg660His) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Childhood Positive MAF is less than 1% rs374143224 no effect on splicing protein is expressed Class C25 (GV: 0.00 - GD: 28.82) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1981T>G r.(1981u>g) p.(Trp661Gly) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 2% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 183.79) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.1987del r.(1987del) p.(Gln663Serfs*33) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 14 c.1993G>A r.(1993g>a) p.(Gly665Arg) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.2003A>G r.(2003a>g) p.(Tyr668Cys) Substitution Substitution Substitution (missense) potentially less severe Uncertain significance Unknown (found only in NBS) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 193.72) Deleterious (score: 0) Disease causing (prob: 1)
exon 14 c.2004C>A r.(2004c>a) p.(Tyr668*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 14 c.2012T>A r.(2012u>a) p.(Met671Lys) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Unknown MAF not reported new weak cryptic splice acceptor unknown Class C35 (GV: 28.53 - GD: 93.42) Deleterious (score: 0.01) Disease causing (p-value: 0.999)
exon 14 c.2012T>G r.(2012u>g) p.(Met671Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Unknown MAF not reported new cryptic splice acceptor unknown Class C35 (GV: 28.53 - GD: 89.59) Deleterious (score: 0.01) Disease causing (p-value: 0.999)
exon 14 c.2014C>T r.(2014c>u) p.(Arg672Trp) Substitution Substitution Substitution (missense) Less severe Likely pathogenic childhood or adult Positive MAF is less than 1% rs757111744 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 101.29) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.2015G>T r.(2015g>u) p.(Arg672Leu) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 101.88) Deleterious (score: 0) Disease causing (prob: 1)
exon 14 c.2015G>A r.(2015g>a) p.(Arg672Gln) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Classic infantile or Childhood Unknown MAF is less than 1% rs778418246 new cryptic splice acceptor unknown Class C35 (GV: 0.00 - GD: 42.81) Deleterious (score: 0) Disease causing (p-value: 1)
exon 14 c.2020C>G r.(2020c>g) p.(His674Asp) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 81.24) Deleterious (score: 0) Disease causing (prob: 1)
exon 14 c.2020C>T r.(2020c>u) p.(His674Tyr) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 83.33) Deleterious (score: 0) Disease causing (prob: 0.999)
exon 14 c.2024_2026del r.(2024_2026del) p.(Asn675del) Deletion Deletion Deletion Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs773958269 no effect on splicing - in frame product protein is expressed
exon 14 c.2024A>G r.(2024a>g) p.(Asn675Ser) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 110.42 - GD: 6.18) Tolerated (score: 0.23) Disease causing (prob: 1)
exon 14 c.2040G>A r.[(2040g>a), r.(spl?)] p.[(=), p.?] Substitution Substitution/ Splicing (splice donor site) Substitution (silent) Less severe Uncertain significance Childhood Unknown MAF not reported weakens exon 14 splice donor unknown
intron 14 c.2040+1G>T r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 14 splice donor unknown
intron 14 c.2040+2dup r.spl p.? duplication duplication/ Splicing (splice donor site) No category very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported weakens splice donor site unknown
intron 14 c.2040+12G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 14 c.2040+20A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304836 no effect on splicing protein is expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 18 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
intron 14 c.2040+20A>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 14 c.2040+22G>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
intron 14 c.2040+29_2190-270del r.spl p.(Pro681_Glu730del) Deletion Deletion Deletion very severe Pathogenic Classic infantile Unknown MAF not reported unknown - causes an in frame product unknown
intron 14 c.2040+66C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304835 no effect on splicing protein is expressed
intron 14 c.2040+69A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304834 no effect on splicing protein is expressed
intron 14 c.2041-64G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304833 no effect on splicing protein is expressed
intron 14 c.2041-61del r.(=) p.? Deletion Deletion (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported unknown protein is expressed
intron 14 c.2041-2A>C r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 15 splice acceptor unknown
intron 14 c.2041-2A>G r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 15 splice acceptor site unknown
intron 14 c.2041-1G>A r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category Very severe Pathogenic Unknown (disease-associated) Unknown MAF is less than 1% rs760731229 loss of exon 15 splice acceptor unknown
exon 15 c.2045A>G r.(2045a>g) p.(Gln682Arg) Substitution Substitution Substitution (missense) Unknown Uncertain significance Classic infantile Positive MAF not reported loss of cryptic splice acceptor protein is expressed Class C0 (GV: 106.82 - GD: 0.00) Tolerated (score: 0.59) Disease causing (p-value: 1)
exon 15 c.2051C>A r.(2051c>a) p.(Pro684Gln) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 75.14) Deleterious (score: 0) Disease causing (prob: 1)
exon 15 c.2051C>G r.(2051c>g) p.(Pro684Arg) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported generates a new cryptic splice donor site unknown Class C65 (GV: 0.00 - GD: 102.71) Deleterious (score: 0) Disease causing (prob: 1)
exon 15 c.2051C>T r.(2051c>u) p.(Pro684Leu) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs147327209 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (prob: 1)
exon 15 c.2055C>A r.(2055c>a) p.(Tyr685*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 15 c.2055C>G r.(2055c>g) p.(Tyr685*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Unknown (found only in NBS) Negative MAF not reported no effect on splicing protein is not expressed
exon 15 c.2056_2057delinsCC r.(2056_2057delinscc) c.2056_2057delinsCC) Deletion/ insertion Deletion/ insertion Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 257.76 - GD: 0.00) Tolerated (score: 0.24)
exon 15 c.2061C>T r.(2061c>u) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 15 c.2065G>A r.2065g>a p.(Glu689Lys) Substitution Substitution Substitution (missense) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800309 no effect on splicing - (frequent background in Asian population) protein is expressed Class C0 (GV: 130.85 - GD: 34.45) Tolerated (score: 0.09) Polymorphism (p-value: 1)
exon 15 c.2066_2070dup r.(2066_2070dup) p.(Ala691Serfs*7) Duplication Duplication Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 15 c.2078dup r.(2078dup) p.(Ala694Glyfs*43) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 15 c.2084dup r.(2084dup) p.(Met695Ilefs*42) Duplication Duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 15 c.2096T>C r.(2096u>c) p.(Leu699Pro) Deletion/ insertion Deletion/ insertion Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 104.11 - GD: 64.34) Deleterious (score: 0.03) Polymorphism (prob: 0.991)
exon 15 c.2097_2102del r.(2097_2102del) p.(Thr700_Leu701del) Deletion Deletion Deletion Potentially less severe Uncertain significance Unknown Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 15 c.2104C>T r.(2104c>u) p.(Arg702Cys) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C25 (GV: 102.71 - GD: 149.78) Deleterious (score: 0) Disease causing (p-value: 1)
exon 15 c.2105G>A r.(2105g>a) p.(Arg702His) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Classic infantile Positive MAF is less than 1% rs398123172 13% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 102.71 - GD: 0.00) Deleterious (score: 0.02) Disease causing (p-value: 1)
exon 15 c.2105G>T r.(2105g>u) p.(Arg702Leu) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0,4% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 102.71 - GD: 56.87) Deleterious (score: 0.03) Disease causing (p-value: 1)
exon 15 c.2109del r.(2109del) p.(Tyr703*) insertion insertion Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 15 c.2114T>C r.(2114u>c) p.(Leu705Pro) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C25 (GV: 30.92 - GD: 68.57) Deleterious (score: 0) Disease causing (p-value: 1)
exon 15 c.2131A>C r.(2131a>c) p.(Thr711Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 57.75 - GD: 24.03) Deleterious (score: 0.01) Disease causing (prob: 1)
exon 15 c.2132C>G r.(2132c>g) p.(Thr711Arg) Substitution Substitution Substitution (missense) Non-pathogenic Uncertain significance Classic infantile Unknown MAF is less than 1% rs759292700 86% residual activity and affects processing in expression study new cryptic splice acceptor unknown Class C15 (GV: 57.75 - GD: 67.34) Deleterious (score: 0) Disease causing (p-value: 1)
exon 15 c.2133A>G r.2133a>g p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800310 no effect on splicing protein is expressed
exon 15 c.2135T>C r.(2135u>c) p.(Leu712Pro) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0,4% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C45 (GV: 14.30 - GD: 86.59) Deleterious (score: 0) Disease causing (p-value: 1)
exon 15 c.2136_2137del r.(2136_2137del) p.(Phe713Profs*23) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 15 c.2140del r.(2140del) p.(His714Thrfs*50) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 15 c.2146G>C r.(2146g>c) p.(Ala716Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported strengthens a cryptic splice acceptor site unknown Class C0 (GV: 99.13 - GD: 1.70) Deleterious (score: 0.02) Disease causing (prob: 1)
exon 15 c.2152G>A r.(2152g>a) p.(Val718Ile) Substitution Substitution Substitution (missense) Non-pathogenic Likely benign Unknown Positive MAF is less than 1% gives 124% residual activity in expression study no effect on splicing protein is expressed Class C0 (GV: 123.92 - GD: 28.68) Tolerated (score: 0.16) Polymorphism (p-value: 1)
exon 15 c.2153_2156delinsACGCCG r.(2153_2156delinsacgccg) p.(Val718Aspfs*47) Deletion/ insertion Deletion/ insertion Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 15 c.2154C>T r.(2154c>u) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
exon 15 c.2161dup r.(2161dup) p.(Glu721Glyfs*16) Duplication Duplication Frameshift Very severe Uncertain significance Unknown Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 19 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 15 c.2161G>T r.(2161g>u) p.(Glu721*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported new weak cryptic splice donor protein is not expressed
exon 15 c.2167G>A r.(2167g>a) p.(Val723Met) Substitution Substitution Substitution (missense) Unknown Uncertain significance Childhood Positive MAF is less than 1% rs767247397 no effect on splicing protein is expressed Class C0 (GV: 234.99 - GD: 0.00) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 15 c.2171C>A r.(2171c>a) p.(Ala724Asp) Substitution Substitution Substitution (missense) Unknown Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 235.10 - GD: 79.30) Deleterious (score: 0.04) Disease causing (p-value: 1)
exon 15 c.2173C>T r.(2173c>u) p.(Arg725Trp) Substitution Substitution Substitution (missense) Less severe Likely pathogenic Childhood or Adult Positive MAF is less than 1% rs121907938 no effect on splicing protein is expressed Class C0 (GV: 127.11 - GD: 65.28) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 15 c.2174G>C r.(2174g>c) p.(Arg725Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 127.11 - GD: 0.00) Tolerated (score: 0.16) Disease causing (p-value: 1)
exon 15 c.2174G>A r.(2174g>a) p.(Arg725Gln) Substitution Substitution Substitution (missense) unknown Uncertain significance Unknown (found only in NBS) Positive MAF is less than 1% rs577042191 no effect on splicing protein is expressed Class C0 (GV: 127.11 - GD: 0.00) Tolerated (score: 0.15) Disease causing (prob: 1)
exon 15 c.2177C>G r.(2177c>g) p.(Pro726Arg) Substitution Substitution Substitution (missense) Unknown Uncertain significance Childhood Positive MAF not reported no effect on splicing protein is expressed Class C35 (GV: 26.87 - GD: 102.09) Deleterious (score: 0.01) Disease causing (p-value: 1)
exon 15 c.2182_2183del r.(2182_2183del) p.(Phe728Profs*8) deletion deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 15 c.2185del r.(2185del) p.(Leu729Trpfs*35) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 15 c.2188G>T r.(2188g>u) p.(Glu730*) Substitution Substitution (splice donor site) Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported new cryptic splice acceptor protein is not expressed
intron 15 c.2189+1G>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Uncertain significance Unknown Unknown MAF not reported loss of exon 15 splice donor unknown
intron 15 c.2189+3G>C r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) No category Very severe Uncertain significance Unknown (disease-associated) Unknown MAF not reported weakens exon 15 splice donor unknown
intron 15 c.2189+95C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs72850840 no effect on splicing protein is expressed
intron 15 c.2189+263G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs7221604 generates a new cyptic splice donor site unknown
intron 15 c.2189+459_3405del r.spl p.? Deletion Deletion Deletion Very severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - causes an in frame product protein is expressed
intron 15 c.2189+510T>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889963 no effect on splicing protein is expressed
intron 15 c.2189+607G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs112710614 no effect on splicing protein is expressed
intron 15 c.2189+616T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs139307163 no effect on splicing protein is expressed
intron 15 c.2189+723G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889819 no effect on splicing protein is expressed
intron 15 c.2189+729A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs74737410 no effect on splicing protein is expressed
intron 15 c.2189+859A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889964 no effect on splicing protein is expressed
intron 15 c.2189+884G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889965 no effect on splicing protein is expressed
intron 15 c.2189+1153A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs72850844 no effect on splicing protein is expressed
intron 15 c.2189+1201C>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs72850846 no effect on splicing protein is expressed
intron 15 c.2189+1208A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs72850847 no effect on splicing protein is expressed
intron 15 c.2189+1263A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs74700450 no effect on splicing protein is expressed
intron 15 c.2189+1290A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs74003630 no effect on splicing protein is expressed
intron 15 c.2189+1600C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs60668271 no effect on splicing protein is expressed
intron 15 c.2190-1531G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs74702528 no effect on splicing protein is expressed
intron 15 c.2190-1463G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs116416508 no effect on splicing protein is expressed
intron 15 c.2190-1139A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs184803352 no effect on splicing protein is expressed
intron 15 c.2190-1005A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889820 no effect on splicing protein is expressed
intron 15 c.2190-686G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs12452616 no effect on splicing protein is expressed
intron 15 c.2190-647G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs59362713 no effect on splicing protein is expressed
intron 15 c.2190-536G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs60429724 no effect on splicing protein is expressed
intron 15 c.2190-490G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs111477580 no effect on splicing protein is expressed
intron 15 c.2190-444A>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889967 no effect on splicing protein is expressed
intron 15 c.2190-336C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs76178719 no effect on splicing protein is expressed
intron 15 c.2190-345A>G r.? p.? Substitution Substitution (intron variant) Insertion potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported partial retention of intron 15 generates a new cryptic splice acceptor site unknown
intron 15 c.2190-53C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 20 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 16 c.2205dup r.(2205dup) p.(Ser736*) Duplication Duplication Substitution (nonsense) very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 16 c.2210C>A r.(2210c>a) p.(Thr737Asn) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 244.82 - GD: 38.84) Tolerated (score: 0.18) Disease causing (p-value: 0.937)
exon 16 c.2213G>A r.(2213g>a) p.(Trp738*) substitution substitution Substitution (nonsense) very severe Pathogenic Classic infantile Negative MAF not reported rs1057516327 no effect on splicing protein is not expressed
exon 16 c.2214G>A r.(2214g>a) p.(Trp738*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 16 c.2219_2220del r.(2219_2220del) p.(Val740Glyfs*55) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 16 c.2221G>A r.(2221g>a) p.(Asp741Asn) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs755272974 no effect on splicing protein is expressed Class C0 (GV: 213.16 - GD: 22.75) Deleterious (score: 0) Disease causing (prob: 1)
exon 16 c.2222A>T r.(2222a>u) p.(Asp741Val) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported rs886044665 generates a new splice acceptor site unknown Class C15 (GV: 213.16 - GD: 119.12) Deleterious (score: 0) Disease causing (prob: 1)
exon 16 c.2227C>A r.(2227c>a) p.(Gln743Lys) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 4,1% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 223.30 - GD: 36.80) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2227C>T r.(2227c>u) p.(Gln743*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 16 c.2228A>G r.(2228a>g) p.(Gln743Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0,8% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 223.30 - GD: 39.51) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2234T>C r.(2234u>c) p.(Leu745Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 248.74 - GD: 29.13) Deleterious (score: 0.01) Disease causing (prob: 1)
exon 16 c.2235dup r.(2235dupg) p.(Trp746Valfs*50) Duplication Duplication Frameshift very severe Pathogenic Classic infantile Unknown MAF not reported generates a new cryptic splice site unknown
exon 16 c.2236T>C r.(2236u>c) p.(Trp746Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF not reported 3,5% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 268.54 - GD: 82.54) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2236T>G r.(2236u>g) p.(Trp746Gly) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 2,1% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 268.54 - GD: 58.26) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2237G>C r.(2237g>c) p.(Trp746Ser) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Childhood Positive MAF not reported 0,1% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 268.54 - GD: 61.50) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2237G>T r.(2237g>u) p.(Trp746Leu) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs752921215 no effect on splicing protein is expressed Class C0 (GV: 268.54 - GD: 8.09) Deleterious (score: 0) Disease causing (prob: 1)
exon 16 c.2237G>A r.(2237g>a) p.(Trp746*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs752921215 no protein on western blot no effect on splicing no endogeneous protein on western blot protein is not expressed
exon 16 c.2238G>C r.(2238g>c) p.(Trp746Cys) Substitution Substitution Substitution (missense) Potentially mild Likely pathogenic Childhood or adult Unknown MAF is less than 1% rs1800312 gives 29,4% residual activity in expression study strengthens a cryptic splice donor site unknown Class C0 (GV: 268.54 - GD: 1.62) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2238G>A r.(2238g>a) p.(Trp746*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs1800312 0% residual activity and affects secretion & processing in expression study no effect on splicing no endogeneous protein on western blot protein is not expressed
exon 16 c.2240G>A r.(2240g>a) p.(Gly747Glu) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 208.58 - GD: 72.02) Deleterious (score: 0.02) Disease causing (prob: 1)
exon 16 c.2242dup r.(2242dup) p.(Glu748Glyfs*48) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs777275355 no effect on splicing - causes an out of frame product protein is not expressed
exon 16 c.2242G>T r.(2242g>u) p.(Glu748*) Substitution Substitution Substitution (nonsense) Very severe Uncertain significance Unknown Negative MAF not reported new cryptic splice donor protein is not expressed
exon 16 c.2255_2257del r.(2255_2257del) p.(Ile752del) Deletion Deletion Deletion Unknown Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 16 c.2261dup r.(2261dup) p.(Val755Serfs*41) Duplication Duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 16 c.2269C>T r.(2269c>u) p.(Gln757*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing protein is not expressed
exon 16 c.2274dup r.(2274dup) p.(Gly759Argfs*37) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 16 c.2276G>C r.(2276g>c) p.(Gly759Ala) Substitution Substitution Substitution (missense) Potentially mild Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 125.13 - GD: 46.95) Tolerated (score: 0.09) Disease causing (p-value: 1)
exon 16 c.2281delinsAT r.(2281delinsau) p.(Ala761Ilefs*35) Deletion/ insertion Deletion/ insertion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 16 c.2284G>A r.(2284g>a) p.(Glu762Lys) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown Unknown MAF is less than 1% rs760063214 strengthens a cryptic splice donor site unknown Class C0 (GV: 117.42 - GD: 36.71) Tolerated (score: 0.08) Polymorphism (p-value: 1)
exon 16 c.2294G>A r.(2294g>a) p.(Gly765Asp) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF not reported rs1292367136 no effect on splicing protein is expressed Class C0 (GV: 126.94 - GD: 78.25) Tolerated (score: 0.08) Disease causing (prob: 0.997)
exon 16 c.2296T>A r.(2296u>a) p.(Tyr766Asn) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs941181575 no effect on splicing protein is expressed Class C0 (GV: 100.30 - GD: 64.77) Tolerated (score: 0.06) Disease causing (prob: 1)
exon 16 c.2297A>C r.(2297a>c) p.(Tyr766Ser) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs144016984 no effect on splicing protein is expressed Class C0 (GV: 100.30 - GD: 57.75) Tolerated (score: 0.12) Disease causing (prob: 1)
exon 16 c.2297A>G r.(2297a>g) p.(Tyr766Cys) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Childhood or adult Positive MAF is less than 1% rs144016984 no effect on splicing protein is expressed Class C25 (GV: 100.30 - GD: 140.37) Deleterious (score: 0.04) Disease causing (p-value: 1)
exon 16 c.2298_2301delinsAAAGTA r.(2298_2301delinsaaagua) p.(Tyr766*) Deletion/ insertion Deletion/ insertion Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported new weak cryptic splice donor protein is not expressed
exon 16 c.2300del r.(2300del) p.(Phe767Serfs*14) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 16 c.2303C>G r.(2303c>g) p.(Pro768Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 102.71) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2303C>T r.(2303c>u) p.(Pro768Leu) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 97.78) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2304del r.(2304del) p.(Leu769Trpfs*12) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 16 c.2314T>C r.(2314u>c) p.(Trp772Arg) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 5% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 268.56 - GD: 82.54) Deleterious (score: 0) Disease causing (p-value: 1)
exon 16 c.2320G>A r.(2320g>a) p.(Asp774Asn) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF is less than 1% rs758390382 loss of a cryptic splice donor site unknown Class C0 (GV: 236.23 - GD: 0.00) Tolerated (score: 0.57) Polymorphism (prob: 1)

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 21 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 16 c.2322_2323insggtgagtctgcaaacggggagt r.(2322_2323insggugagucugcaaacggggagu) p.(Asp774Glufs*14) Insertion Insertion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported new cryptic splice donor - causes an out of frame product protein is not expressed
exon 16 c.2326C>T r.(2326c>u) p.(Gln776*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
intron 16 c.2331+1G>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of exon 16 splice donor unknown
intron 16 c.2331+2T>C r.2316_2331del p.(Tyr773fs*3) Substitution Substitution/ Splicing (splice donor site) Frameshift Very severe Pathogenic Classic infantile Unknown MAF not reported causes skip of the last 16bp of exon 16 loss of exon 16 splice donor - causes an out of frame product unknown
intron 16 c.2331+2T>A r.[2315_2331delins2332-109_2332-1 ,2315_2331del] p.[Trp772Cysfs*40, Trp772Cysfs*18] Substitution Substitution/ Splicing (splice donor site) Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot, causes partial skipping of exon 16 and partial inclu ... loss of exon 16 splice donor no endogeneous protein on western blot unknown
intron 16 c.2331+4A>G r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) No category Less severe Uncertain significance Unknown (disease-associated) Unknown MAF not reported weakens exon 16 splice donor unknown
intron 16 c.2331+5G>C r.(spl?) p.? substitution Substitution/ Splicing (intron variant) No category very severe Unknown significance Classic infantile Unknown MAF not reported weakens exon 16 splice donor site unknown
intron 16 c.2331+20G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304832 no effect on splicing protein is expressed
intron 16 c.2331+24T>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2304831 no effect on splicing protein is expressed
intron 16 c.2331+102del r.?) p.? Deletion Deletion (intron variant) No category presumably non pathogenic Unknown significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed
intron 16 c.2331+151C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs111537160 no effect on splicing protein is expressed
intron 16 c.2332-198A>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs2304830 no effect on splicing protein is expressed
exon 17 c.2334_2335dup r.(2334_2335dup) p.(Pro779Argfs*3) duplication duplication Frameshift very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported weakens a cryptic splice donor site unknown
exon 17 c.2338G>A r.2338g>a p.(Val780Ile) Substitution Substitution Substitution (missense) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1126690 no effect on splicing protein is expressed Class C0 (GV: 353.86 - GD: 0.00) Tolerated (score: 0.97) Polymorphism (p-value: 1)
exon 17 c.2357dup r.(2357dup) p.(Pro788Thrfs*8) Duplication Duplication Frameshift Very severe Uncertain significance Unknown Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 17 c.2373_2376delinsTGCTCA r.(2373_2376delinsugcuca) p.(Pro793Hisfs*14) Deletion/ insertion Deletion/ insertion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 17 c.2377_2378insAC r.(2377_2378insAC) p.(Pro793Hisfs*14) insertion insertion Frameshift very severe Pathogenic Classic infantile Unknown MAF not reported strengthens a cryptic splice donor site unknown
exon 17 c.2380del r.(2380del) p.(Arg794fs*12) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 17 c.2380dup r.(2380dup) p.(Arg794Profs*2) duplication duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 17 c.2385del r.(2385del) p.(Glu795Aspfs*11) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported strengthens cryptic splice acceptor - causes an out of frame product protein is not expressed
exon 17 c.2395C>G r.(2395c>g) p.(His799Asp) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 249.90 - GD: 40.46) Tolerated (score: 0.3) Polymorphism (p-value: 0.88)
exon 17 c.2395C>T r.(2395c>u) p.(His799Tyr) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs143347747 no effect on splicing protein is expressed Class C0 (GV: 249.90 - GD: 25.33) Tolerated (score: 0.69) Polymorphism (prob: 0.952)
exon 17 c.2407_2412del r.(2407_2412del) p.(Gln803_Trp804del) Deletion Deletion Deletion Unknown Likely pathogenic Childhood Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 17 c.2407C>T r.(2407c>u) p.(Gln803*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Unknown MAF is less than 1% rs1344266804 generates a new cryptic splice donor site unknown
exon 17 c.2408_2426del r.(2408_2426del) p.(Gln803Profs*39) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs763048948 loss of 2 cryptic splice donors - causes an out of frame product protein is not expressed
exon 17 c.2411G>A r.(2411g>a) p.(Trp804*) substitution substitution Substitution (nonsense) very severe Pathogenic Classic infantile Unknown MAF not reported strenghens two cryptic splice donor sites unknown
exon 17 c.2431dup r.(2431dup) p.(Leu811Profs*73) Duplication Duplication Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 17 c.2431del r.(2431del) p.(Leu811Trpfs*37) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 17 c.2432del r.(2432del) p.(Leu811fs*36) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs766560578 no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 17 c.2439dup r.(2439dup) p.(Ile814Hisfs*70) Duplication Duplication Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 17 c.2446G>A r.2446g>a p.(Val816Ile) Substitution Substitution Substitution (missense) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800314 no effect on splicing protein is expressed Class C0 (GV: 235.27 - GD: 0.00) Tolerated (score: 0.35) Polymorphism (p-value: 0.999)
exon 17 c.2456G>C r.(2456g>c) p.(Arg819Pro) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0,4% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 243.06 - GD: 40.46) Deleterious (score: 0.02) Disease causing (p-value: 1)
exon 17 c.2459_2461del r.(2459_2461del) p.(Ala820del) deletion deletion deletion Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs1182634884 no effect on splicing - causes an in frame product protein is expressed
exon 17 c.2460dup r.(2460dup) p.(Gly821Trpfs*63) duplication duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 17 c.2474C>G r.(2474c>g) p.(Pro825Arg) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported rs886042703 strenghens a cryptic splice acceptor unknown Class C25 (GV: 37.56 - GD: 70.85) Deleterious (score: 0.02) Disease causing (prob: 1)
exon 17 c.2480A>G r.(2480a>g) p.(Gln827Arg) Substitution Substitution/ Splicing (splice donor site) Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Unknown MAF not reported weakens exon 17 splice donor sire and loss of a cryptic splice acceptor site unknown Class C0 (GV: 53.23 - GD: 5.07) Tolerated (score: 0.08) Disease causing (prob: 1)
intron 17 c.2481+1G>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Uncertain significance Childhood Unknown MAF not reported loss of cryptic splice donor unknown
intron 17 c.2481+2T>C r.[2331_2332ins2332-109_2332-1; 2462_2481del, 2462_2481del, 2332_2481del] p.[Val778AlaSerTer, Tyr822Profs*55, Val778_Gln827del] Substitution Substitution/ Splicing (splice donor site) Frameshift Very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported causes partial inclusion of intron 16 and partial skipping of exon 17 loss of exon 17 splice donor unknown
intron 17 c.2481+110_2646+39del r.2482_2646del p.(Gly828_Asn882del) Deletion Deletion Deletion Very severe Pathogenic Classic infantile Positive MAF not reported causes an in frame skip of exon 18 no effect on splicing - causes an in frame skip of exon 18 endogenous protein on western blot protein is expressed
intron 17 c.2482-132C>T r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs113824706 no effect on splicing protein is expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 22 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
intron 17 c.2482-5T>C r.? p.? Substitution Substitution (intron variant) No category unknown Unknown significance Unknown (found only in NBS) Positive MAF not reported rs1290870969 no effect on splicing protein is expressed
intron 17 c.2482-2A>G r.spl p.? Substitution Substitution/ Splicing (splice acceptor site) No category unknown Pathogenic Unknown (found only in NBS) Unknown MAF is less than 1% rs756671283 loss of exon 18 splice acceptor site Unknown
exon 18 c.2495_2496del r.(2495_2496del) p.(Thr832Asnfs*51) Deletion Deletion Frameshift Very severe Uncertain significance Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 18 c.2501_2502del r.(2501_2502del) p.(Thr834Argfs*49) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 18 c.2512C>T r.(2512c>u) p.(Gln838*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs369532274 no effect on splicing protein is not expressed
exon 18 c.2515C>T r.(2515c>u) p.(Gln839*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing protein is not expressed
exon 18 c.2528T>C r.(2528u>c) p.(Leu843Pro) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF is less than 1% rs775524898 no effect on splicing protein is expressed Class C65 (GV: 4.86 - GD: 95.38) Deleterious (score: 0) Disease causing (p-value: 1)
exon 18 c.2530_2541del r.(2530_2541del) p.(Arg844_Leu847del) Deletion Deletion Deletion Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 18 c.2537C>A r.(2537c>a) p.(Ala846Asp) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 60.00 - GD: 81.64) Deleterious (score: 0.01) Disease causing (prob: 0.999)
exon 18 c.2544del r.(2544del) p.(Lys849Argfs*38) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs1370343888 no effect on splicing - causes an out of frame product protein is not expressed
exon 18 c.2553G>A r.2553g>a p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1042397 weakens a cryptic splice donor site protein is expressed
exon 18 c.2560C>T r.(2560c>u) p.(Arg854*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs121907943 no protein on western blot no effect on splicing no endogeneous protein on western blot protein is not expressed
exon 18 c.2563G>C r.(2563g>c) p.(Gly855Arg) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs1341804179 no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (prob: 1)
exon 18 c.2578G>A r.(2578g>a) p.(Asp860Asn) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 0.00 - GD: 23.01) Deleterious (score: 0) Disease causing (prob: 1)
exon 18 c.2584G>A r.(2584g>a) p.(Gly862Arg) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Childhood Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 125.13) Deleterious (score: 0) Disease causing (prob: 1)
exon 18 c.2585del r.(2585del) p.(Gly862Glufs*25) deletion deletion Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 18 c.2596del r.(2596del) p.(Glu866Lysfs*21) deletion deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 18 c.2600_2604delinsA r.(2600_2604delinsa) p.(Val867Glufs*19) Deletion/ insertion Deletion/ insertion Frameshift Very severe Pathogenic Classic infantile or Childhood Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 18 c.2605del r.(2605del) p.(Glu869Serfs*18) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 18 c.2608C>T r.(2608c>u) p.(Arg870*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs780321415 no protein on western blot new weak cryptic splice donor no endogeneous protein on western blot protein is not expressed
exon 18 c.2619C>G r.(2619c>g) p.(Tyr873*) Substitution Substitution Substitution (nonsense) very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported loss of a cryptic splice acceptor site unknown
exon 18 c.2636T>C r.(2636u>c) p.(Leu879Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Classic infantile Positive MAF is less than 1% rs1319326794 no effect on splicing protein is expressed Class C0 (GV: 156.90 - GD: 0.00) Deleterious (score: 0.03) Disease causing (prob: 0.994)
exon 18 c.2639C>A r.(2639c>a) p.(Ala880Asp) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Classic infantile Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 112.58 - GD: 123.57) Tolerated (score: 0.08) Disease causing (p-value: 1)
exon 18 c.2646_2646+1del r.spl p.? Deletion Deletion/ Splicing (splice donor site) Frameshift Very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported no effect on splicing - causes an out of frame product unknown
intron 18 c.2646+2T>A r.spl p.? Substitution Substitution/ Splicing (splice donor site) No category Very severe Pathogenic Classic infantile Unknown MAF not reported loss of exon 18 splice donor unknown
intron 18 c.2646+39G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% rs41292410 no effect on splicing protein is expressed
intron 18 c.2647-71G>C r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs4889821 no effect on splicing protein is expressed
intron 18 c.2647-23del r.? p.? Deletion Deletion (intron variant) No category unknown Unknown significance Unknown (found only in NBS) Positive MAF is less than 1% rs749000061 no effect on splicing protein is expressed
intron 18 c.2647-20T>G r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) No category Unknown Uncertain significance Unknown (disease-associated) Unknown MAF not reported new cryptic splice acceptor unknown
intron 18 c.2647-7G>A r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) No category Potentially mild Uncertain significance Adult Unknown MAF is less than 1% rs192679574 new cryptic splice acceptor unknown
exon 19 c.2655_2656del r.(2655_2656del) p.(Val886Glufs*2) Deletion Deletion Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 19 c.2662G>T r.(2662g>u) p.(Glu888*) Substitution Substitution Substitution (nonsense) Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs765718882 no effect on splicing protein is not expressed
exon 19 c.2702T>A r.(2702u>a) p.(Leu901Gln) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Childhood Positive MAF not reported affects processing in expression study no effect on splicing protein is expressed Class C0 (GV: 98.69 - GD: 24.08) Deleterious (score: 0.04) Disease causing (p-value: 1)
exon 19 c.2706del r.(2706del) p.(Lys903Argfs*2) Deletion Deletion Frameshift Very severe Pathogenic Unknown (disease-associated) Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 19 c.2707_2709del r.(2707_2709del) p.(Lys903del) Deletion Deletion Deletion Very severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 19 c.2716G>A r.(2716g>a) p.(Val906Ile) substitution substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 148.91 - GD: 0.00) Tolerated (score: 0.68) Disease causing (prob: 0.895)
exon 19 c.2720T>C r.(2720u>c) p.(Leu907Pro) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C0 (GV: 108.34 - GD: 28.88) Tolerated (score: 0.07) Disease causing (prob: 1)
exon 19 c.2724C>G r.(2724c>g) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 19 c.2725G>A r.(2725g>a) p.(Val909Met) Substitution Substitution Substitution (missense) potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF is less than 1% rs138407065 no effect on splicing protein is expressed Class C0 (GV: 30.92 - GD: 0.00) Deleterious (score: 0.01) Disease causing (prob: 0.998)
exon 19 c.2738C>G r.(2738c>g) p.(Pro913Arg) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 73.35 - GD: 95.06) Deleterious (score: 0.01) Disease causing (p-value: 1)

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl

Pompe disease GAA variant database

Variant database

Page 23 of 23
Location DNA nomenclature RNA nomenclature Protein nomenclature Type of variant DNA Type of variant RNA Type of variant Protein Predicted severity ACMG classification Phenotype with null allele CRIM status MAF RS number Biochemical evidence of pathogenicity Splicing and translation prediction Biochemical evidence of CRIM status Prediction of CRIM status Missense prediction (Align GVGD) Missense prediction (SIFT) Missense prediction (Mutation Taster)
exon 19 c.2740dup r.(2740dup) p.(Gln914Profs*104) duplication duplication Frameshift very severe Pathogenic Unknown (disease-associated) Negative MAF is less than 1% rs745427943 no effect on splicing - causes an out of frame product protein is not expressed
exon 19 c.2741delinsCAG r.(2741delinscag) p.(Gln914fs*30) Deletion/ insertion Deletion/ insertion Frameshift Very severe Pathogenic Classic infantile Negative MAF not reported no protein on western blot no effect on splicing - causes an out of frame product no endogeneous protein on western blot protein is not expressed
exon 19 c.2742dup r.(2742dup) p.(Gln915Alafs*103) Duplication Duplication Frameshift very severe Pathogenic Classic infantile Negative MAF is less than 1% rs771642865 no effect on splicing - causes an out of frame product protein is not expressed
exon 19 c.2744A>C r.(2744a>c) p.(Gln915Pro) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Unknown MAF not reported new weak cryptic splice acceptor unknown Class C0 (GV: 166.33 - GD: 0.00) Tolerated (score: 0.22) Disease causing (p-value: 0.825)
exon 19 c.2746G>T r.(2746g>u) p.(Val916Phe) Substitution Substitution Substitution (missense) Potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported 0% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C45 (GV: 0.00 - GD: 48.95) Deleterious (score: 0) Disease causing (p-value: 1)
exon 19 c.2757del r.(2757del) p.(Asn919Lysfs*24) deletion deletion Frameshift very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported strengthens a cryptic splice donor site - causes an out of frame product unknown
exon 19 c.2758_2775dup r.(2758_2775dup) p.(ly920_Asn925dup) Duplication Duplication Duplication Very severe Likely pathogenic Classic infantile Positive MAF not reported no effect on splicing - in frame product protein is expressed
exon 19 c.2770T>C r.(2770u>c) p.(Ser924Pro) Substitution Substitution Substitution (missense) Non-pathogenic Likely benign Unknown Positive MAF not reported 167% residual activity and affects secretion in expression study no effect on splicing protein is expressed Class C0 (GV: 130.87 - GD: 0.00) Tolerated (score: 0.24) Polymorphism (p-value: 0.997)
exon 19 c.2780C>T r.2780c>u p.(Thr927Ile) Substitution Substitution Substitution (missense) Non-pathogenic Benign Unknown Positive MAF is over 5% rs1800315 no effect on splicing protein is expressed Class C15 (GV: 57.75 - GD: 89.28) Deleterious (score: 0.01) Polymorphism (p-value: 0.863)
exon 19 c.2783A>G r.(2783a>g) p.(Tyr928Cys) Substitution Substitution Substitution (missense) Unknown Uncertain significance Unknown (disease-associated) Positive MAF not reported no effect on splicing protein is expressed Class C65 (GV: 0.00 - GD: 193.72) Deleterious (score: 0) Disease causing (p-value: 0.953)
intron 19 c.2799+4A>G r.(spl?) p.? Substitution Substitution/ Splicing (intron variant) No category Unknown Uncertain significance Adult Unknown MAF is less than 1% rs778032599 no effect on splicing unknown
intron 19 c.2799+5G>A r.(spl?) p.? substitution Substitution/ Splicing (intron variant) No category very severe Pathogenic Unknown (disease-associated) Unknown MAF not reported no effect on splicing unknown
intron 19 c.2800-60G>A r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF is less than 1% no effect on splicing protein is expressed
intron 19 c.2800-227C>G r.(=) p.? Substitution Substitution (intron variant) No category Non-pathogenic Likely benign Unknown Positive MAF is over 1% rs9890469 no effect on splicing protein is expressed
intron 19 c.2800-4C>G r.(=) p.? Substitution Substitution (intron variant) No category Unknown Uncertain significance Unknown (disease-associated) Unknown MAF not reported no effect on splicing unknown
intron 19 c.2800-1G>C r.spl p.? substitution Substitution/ Splicing (splice acceptor site) No category very severe Pathogenic Classic infantile Unknown MAF is less than 1% rs1328159128 loss of splice accepter site and generation of a new cryptic splice accepter sit ... unknown
exon 20 c.2804T>C r.(2804u>c) p.(Leu935Pro) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Unknown Positive MAF not reported 0,5% residual activity and affects secretion & processing in expression study no effect on splicing protein is expressed Class C0 (GV: 242.23 - GD: 0.00) Deleterious (score: 0.02) Disease causing (p-value: 1)
exon 20 c.2808C>T r.(2808c>u) p.(=) Substitution Substitution Substitution (silent) Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 20 c.2815_2816del r.(2815_2816del) p.(Val939Leufs*78) Deletion Deletion Frameshift Very severe Pathogenic Classic infantile Negative MAF is less than 1% rs763359208 no effect on splicing - causes an out of frame product protein is not expressed
exon 20 c.2843dup r.(2843dup) p.(Val949Argfs*69) Duplication Duplication Frameshift very severe Pathogenic Classic infantile Negative MAF not reported no effect on splicing - causes an out of frame product protein is not expressed
exon 20 c.2845_2847del r.(2845_2847del) p.(Val949del) Deletion Deletion Deletion potentially less severe Likely pathogenic Unknown (disease-associated) Positive MAF not reported no effect on splicing - causes an in frame product protein is expressed
exon 20 c.2846T>A r.(2846u>a) p.(Val949Asp) Substitution Substitution Substitution (missense) Potentially less severe Uncertain significance Childhood Positive MAF not reported no effect on splicing protein is expressed Class C15 (GV: 234.99 - GD: 114.90) Deleterious (score: 0) Disease causing (p-value: 0.588)
exon 20, 3' UTR c.*3G>A r.(*3g>a) p.? Substitution Substitution No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 20, 3' UTR c.*16T>A r.(*16u>a) p.? Substitution Substitution No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 20, 3' UTR c.*91G>A r.(*91g>a) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs2229221 no effect on splicing protein is expressed
exon 20, 3' UTR c.*140del r.(*140del) p.? Deletion Deletion (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 20, 3' UTR c.*143C>T r.(*143c>u) p.? Substitution Substitution No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 20, 3' UTR c.*154_*155insG r.(*154_*155insg) p.? Insertion Insertion (intron variant) No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 20, 3' UTR c.*223C>T r.(*223c>u) p.? Substitution Substitution (intron variant) No category Non-pathogenic Benign Unknown Positive MAF is over 5% rs8132 no effect on splicing protein is expressed
exon 20, 3' UTR c.*227G>C r.(*227g>c) p.? Substitution Substitution No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed
exon 20, 3' UTR c.*418T>C r.(*418u>c) p.? Substitution Substitution No category Non-pathogenic Uncertain significance Unknown Positive MAF not reported no effect on splicing protein is expressed

The Pompe disease GAA variant database represents an effort to collect all known variants in the GAA gene and is maintained and provide by the Pompe center, Erasmus MC.

We kindly ask you to reference one of the following articles if you use this database for research purposes:

de Faria, DOS, in 't Groen, SLM, Bergsma, AJ, et al. Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.
Human Mutation. 2021; 42: 119-134. https://doi.org/10.1002/humu.24148

Niño, MY, in 't Groen, SLM, Hoogeveen-Westerveld, M, et al. Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity. Human Mutation. 2019; 40: 1954–1967. https://doi.org/10.1002/humu.23854

www.pompecenter.nl