GAA p.Ala486Pro

The NM_000152.5:c.1456G>C variant in GAA is a missense variant predicted to cause substitution of alanine by proline at amino acid 486 (p.Ala486Pro). At least four individuals with this variant have been reported to have a diagnosis of Pompe disease. One individual was reported to have clinical features consistent with infantile-onset Pompe disease (IOPD), was on enzyme replacement therapy for Pompe disease, and was homozygous for this variant (PMIDs: 25626711, 27927596) (PP4_Moderate). Three individuals were reported to have late-onset Pompe disease (LOPD), but the reported information did not meet criteria for PP4. All three individuals with a diagnosis of LOPD were compound heterozygous for the variant and c.-32-13T>G, which is classified as pathogenic by the ClinGen LD VCEP, phase unconfirmed (PMIDs: 19588081, 26350092, 40714860) (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001695 (2/1180014 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). Expression of the variant in COS-7 or HEK293 cells resulted in 0% wild type GAA activity in cells and 3.0% in medium and evidence of abnormal GAA synthesis and processing on Western blot, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 22644586) (PS3_Moderate). Additionally, the computational predictor REVEL gives a score of 0.765, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Three other missense variants in the same codon (c.1456G>A (p.Ala486Thr), c.1456G>T (p.Ala486Ser), and c.1457C>T (p.Ala486Val)) have been reported in ClinVar. However, these variants have not yet been evaluated by the ClinGen Lysosomal Diseases VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): PS3_Moderate, PM2_Supporting, PM3, PP3, PP4_Moderate. (Classififcation approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 6, 2026)