GAA p.Val548Phe

The NM_000152.5:c.1642G>T variant in GAA is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 548 (p.Val548Phe). This variant has been observed in cis with the variant c.1880C>T (p.Ser627Phe) (PMID 28763149, ClinVar #000597382.19), which is classified as pathogenic by ClinGen LD VCEP, in two individuals with Pompe disease. The phase of variant was confirmed by parental testing (BP2). The computational predictor REVEL gives a score of 0.269, which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). This variant is absent in gnomAD v4.1.0, meeting this criterion (PM2_Supporting). Expression of the variant in HEK293 cells resulted in normal activity and processing, indicating that variant does not impact protein function ((unpublished data from the laboratory that published PMID: 36246652) (BS3_supporting). There is a ClinVar entry for this variant (Variation ID: 597381). Although PM2_Supporting is met, this is the only pathogenic criterion that was met. Overall, the evidence indicates that this variant is likely benign (BS3_Supporting, BP2, BP4) and thus the ClinGen LD VCEP classified this variant as likely benign. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS3_supporting, BP2, BP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 3, 2025)