Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000152.5(GAA):c.1562A>T (p.Glu521Val)

CA401367205

972760 (ClinVar)

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: baaa2e82-4341-4b56-894f-b9546270aa06

Approved on: 2025-12-16

Published on: 2025-12-16

HGVS expressions

NM_000152.5(GAA):c.1562A>T (p.Glu521Val)

NM_000152.5:c.1562A>T

NC_000017.11:g.80110951A>T

CM000679.2:g.80110951A>T

NC_000017.10:g.78084750A>T

CM000679.1:g.78084750A>T

NC_000017.9:g.75699345A>T

NG_009822.1:g.14396A>T

ENST00000570803.6:c.1562A>T

ENST00000572080.2:c.1562A>T

ENST00000577106.6:c.1562A>T

ENST00000302262.8:c.1562A>T

ENST00000302262.7:c.1562A>T

ENST00000390015.7:c.1562A>T

NM_000152.3:c.1562A>T

NM_001079803.1:c.1562A>T

NM_001079804.1:c.1562A>T

NM_000152.4:c.1562A>T

NM_001079803.2:c.1562A>T

NM_001079804.2:c.1562A>T

NM_001079803.3:c.1562A>T

NM_001079804.3:c.1562A>T

Pathogenic

PM2_Supporting PP3 PP4_Moderate PM5 PM3_Strong

Evidence Links 0

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1562A>T variant in GAA is a missense variant predicted to cause substitution of glutamic acid by valine at amino acid 521 (p.Glu521Val). At least six individuals diagnosed with Pompe disease have been reported to have this variant, including one individual with clinical features consistent with infantile-onset Pompe disease and on enzyme replacement therapy (PMID: 35833019), one individual with GAA activity in the affected range in dried blood spot (PMID: 34072668), two individuals with GAA activity reported to be deficient but the data were not provided (PMID: 39010129), and two individuals with muscle histology consistent with Pompe disease (PMIDs: 25526786, 29786057) (PP4_Moderate). Five of these individuals were compound heterozygous for this variant and another pathogenic/likely pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID: 34072668), c.796C>T (p.Pro266Ser) (PMID: 35833019), c.1309C>T (p.Arg437Cys) (PMID: 29786057), c.1781G>A (p.Arg594His) (PMID: 25526786), and c.2238G>C (p.Trp746Cys) (PMID: 39010129) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002228 (1/44878 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.992 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Additionally, another missense variant in the same codon, c.1561G>A (p.Glu521Lys) (ClinVar Variation ID: 4022), has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Strong, PM5, PP3, PP4_Moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 16, 2025)

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002228 (1/44878 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.992 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).

PP4_Moderate

At least six individuals diagnosed with Pompe disease have been reported to have this variant including one individual with clinical features consistent with infantile-onset Pompe disease and on enzyme replacement therapy (PMID: 35833019), one individual with GAA activity in the affected range in dried blood spot (PMID: 34072668), two individuals with GAA activity reported to be deficient but the data were not provided (PMID: 39010129), and two individuals with muscle histology consistent with Pompe disease (PMIDs: 25526786, 29786057) (PP4_Moderate).

PM5

Another missense variant in the same codon, c.1561G>A (p.Glu521Lys) (ClinVar Variation ID: 4022), has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5).

PM3_Strong

This variant has been detected in at least five individuals with Pompe disease who were compound heterozygous for this variant and another pathogenic/likely pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID: 34072668) (0.5 points), c.796C>T (p.Pro266Ser) (PMID: 35833019) (0.25 points), c.1309C>T (p.Arg437Cys) (PMID: 29786057) (0.5 points), c.1781G>A (p.Arg594His) (PMID: 25526786) (0.25 points), and c.2238G>C (p.Trp746Cys) (PMID: 39010129) (0.5 points). (Total of 2.0 points; PM3_Strong).

Curation History

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