GAA p.Pro493Ser

The NM_000152.5:c.1477C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 493 (p.Pro493Ser). This variant has been detected in at least 1 patient reported to have Pompe disease with reported laboratory values demonstrating deficient GAA activity (Duke University; PMID: 31904026, 32518148) (PP4_moderate). This variant has been detected in at least one individual with Pompe disease. This individual was compound heterozygous for the variant, c.1477C>T (p.Pro493Ser), and two other variants: a variant classified as pathogenic by the ClinGen LD VCEP, c.1978C>T (p.Arg660Cys) (ClinVar Variation ID: 558604, SCV002540656.1), and a variant not classified by the by the ClinGen LD VCEP, c.2221G>A (p.Asp741Asn) (ClinVar Variation ID: 571521) (Duke University; PMID: 31904026, 32518148). The c.1477C>T (p.Pro493Ser) variant was confirmed in trans with the c.1978C>T (p.Arg660Cys) and c.2221G>A (p.Asp741Asn). The phase of these variants was confirmed in trans by parental testing (PM3_not met). Another missense variant, c.1478C>T, p.Pro493Leu (ClinVar Variation ID: 379593) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_supporting). This variant is absent in gnomAD v4.1.0 (PM2_Supporting). Residual in vitro enzyme activity for the variant in 2 replicates resulted in a mean of 12.3% wild type GAA activity (within the pathogenic control range of <15%), indicating that this variant may impact protein function (Duke University) (PS3_Supporting). The computational predictor REVEL gives a score of 0.781 which is above the threshold predicting a damaging (>0.7) impact on GAA function (PP3_met). There is a ClinVar entry for this variant (Variation ID: 2160730; 1 star review status) with one submitter classifying the variant as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP4_Moderate, PP3_met, PM2_supporting, PM5_supporting, PS3_supporting, PM3_not met). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 6, 2025).