The NM_000152.5:c.896T>G variant in GAA is a missense variant predicted to cause substitution of leucine by arginine at amino acid 299 (p.Leu299Arg). At least two individuals with this variant have been reported to have a diagnosis of Pompe disease. One of these individuals was diagnosed with late-onset Pompe disease and had documented GAA deficiency with <10% of normal mean control level of GAA activity in muscle and was on enzyme replacement therapy for Pompe disease. This individual was compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LD VCEP, c.1655T>C (p.Leu552Pro), phase unconfirmed (PMID: 38313679, Duke University Medical Center). Another individual with this variant was reported to have infantile-onset Pompe disease with <10% of normal mean control level of GAA activity in cultured fibroblasts, but exact values for the individual's GAA activity and laboratory control values for GAA activity were not provided. This individual was compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LD VCEP, a deletion of exon 18 (c.2481+110_2646+39del), phase unconfirmed (PMIDs: 7603531, 7717400) (PM3, PP4_Moderate). This variant is absent in gnomAD v4.1.1 (PM2_Supporting). Expression of the variant in COS-7 cells resulted in <2% wild type GAA activity, indicating that this variant may impact protein function (PMID: 19862843). Additionally, expression of the variant in TR4219 cells resulted in "complete loss of GAA activity". One positive and multiple negative controls were included, the experiment was replicated, and the cells were sequenced to ensure integrity of the variant (PMID: 7717400) (PS3_Supporting). The computational predictor REVEL gives a score of 0.93 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant in the same codon, c.896T>C (p.Leu299Pro) (ClinVar Variation ID: 180144), has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 4025). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PS3_Supporting, PM2_Supporting, PM3, PM5, PP3, and PP4_Moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 1, 2026).