GAA p.Val642Phe

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)