GAA p.Pro482Arg

The NM_000152.5:c.1445C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 482 (p.Pro482Arg). One proband with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID: 31392188) (PP4). This variant has been detected two apparently unrelated probands and one sibling with late onset Pompe disease who were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP, c.-32-13T>G; the phase is unknown (PMID: 24383498, 29122469, 31392188, 31710733, 38313679); 2 x 0.5pt) (PM3). This variant is absent in gnomAD v4.1.0.. (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.948 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other missense variants at the same amino acids have been reported in patients with Pompe disease; c.1445C>T (p.Pro482Leu) (ClinVar Variation ID: 982297) has been classified as likely pathogenic by the ClinGen LD VCEP, c.1444C>T (p.Pro482Ser) has not yet been classified by the VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 1067574). 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 LD VCEP (Specifications Version 2.0.0): PM3, PS3_Moderate, PP3, PP4, PM2_Supporting, PM5_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 28, 2025).