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.1924G>T (p.Val642Phe)

CA401369892

2675763 (ClinVar)

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: 3aff7972-13bd-4a43-b58c-e918dbd25494

Approved on: 2026-04-07

Published on: 2026-04-08

HGVS expressions

NM_000152.5(GAA):c.1924G>T (p.Val642Phe)

NM_000152.5:c.1924G>T

NC_000017.11:g.80112911G>T

CM000679.2:g.80112911G>T

NC_000017.10:g.78086710G>T

CM000679.1:g.78086710G>T

NC_000017.9:g.75701305G>T

NG_009822.1:g.16356G>T

ENST00000570803.6:c.1924G>T

ENST00000572080.2:c.*62G>T

ENST00000577106.6:c.1924G>T

ENST00000302262.8:c.1924G>T

ENST00000302262.7:c.1924G>T

ENST00000390015.7:c.1924G>T

ENST00000570716.1:n.364G>T

ENST00000572080.1:c.343G>T

ENST00000572803.1:n.538G>T

NM_000152.3:c.1924G>T

NM_001079803.1:c.1924G>T

NM_001079804.1:c.1924G>T

NM_000152.4:c.1924G>T

NM_001079803.2:c.1924G>T

NM_001079804.2:c.1924G>T

NM_001079803.3:c.1924G>T

NM_001079804.3:c.1924G>T

Uncertain Significance

PP4 PP3 PM3 PM2_Supporting

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.1924G>T variant in GAA is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 642 (p.Val642Phe). One proband with symptoms consistent with infantile-onset Pompe disease has been reported (PMID: 26310554). A second proband with a reported diagnosis of infantile-onset Pompe disease has also been reported, but clinical features were not documented (PMID: 29122469). Both probands are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.2105G>A (p.Arg702His) (PMID: 26310554) and c.1210G>A (p.Asp404Asn) (PMID: 29122469) (PM3). The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.0000008483 (1/1178846 alleles) in the European (non-Finnish) 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 0.946 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 2675763). In summary, this variant meets the criteria to be classified as uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP3, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 7, 2026)

PP4

One individual who harbors this variant was identified via carrier screening. One patient with this variant was diagnosed with Pompe disease but GAA activity levels and documentation of symptoms were not reported. A second patient with this variant was diagnosed with Pompe disease and reported to have cardiomyopathy, hepatosplenomegaly, and respiratory insufficiency (PP4).

PP3

The computational predictor REVEL gives a score of [0.X] which is above the threshold of 0.946, evidence that correlates with impact to GAA function (PP3).

PM3

This variant has been detected in three individuals with Pompe disease. One individual who harbrors this variant was identified via carrier screening. Two individuals were compound heterozygous for the variant and a pathogenic variant but phase was not confirmed for either patient (PM3_Supporting).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 0.0000008483 (1/1178846 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

Curation History

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