GAA p.Arg464Ser

The NM_000152.5c.1392G>C variant in GAA is a missense variant predicted to cause substitution of Arginine by Serine at amino acid 464 (p.Arg464Ser). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00019 (219/1179922 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.631 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Another missense variant c.1390A>T, p.Arg464Trp in the same codon has been reported in a patient with Pompe disease (ClinVar Variation ID: 843677). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 432217, 3-star review status) with 6 submitters classifying the variant as Uncertain Significance and 1 submitter classifying the variant as Likely Pathogenic. In summary, this variant meets the criteria to be classified as Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Disease Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. (Classification approved by the ClinGen Lysosomal Disease Variant Curation Expert Panel on November 17, 2025)