The NM_000152.5:c.953T>A variant in GAA is a missense variant predicted to cause substitution of methionine by lysine at amino acid 318 (p.Met318Lys). At least 3 patients with this variant were diagnosed with Pompe disease and had documented laboratory values showing GAA deficiency with in dried blood spot, or <1% GAA activity in fibroblasts (PMID: 18425781, 21484825, 36237614) (PP4_Moderate). Of those individuals, one was compound heterozygous for the variant and another variant in GAA that has been classified by the ClinGen LD VCEP as pathogenic for Pompe disease, c.1822C>T (p.Arg608Ter); the phase is unknown (PMID 21484825) (0.5 pt), and two patients, assumed to be unrelated, are homozygous for the variant (2 x 0.5 pt). Total 1.5 pts (PM3). This variant is absent from gnomAD v4.1.0. (PM2_Supporting). Expression of the variant in COS cells resulted in 3.2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.926 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at the same amino acid position, c.953T>C (p.Met318Thr) (ClinVar Variation ID: 4021) has been classified as pathogenic by the ClinGen LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 558700). 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): PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 1, 2026)