The NM_000152.5:c.925G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 309 (p.Gly309Arg). In a cohort of 54 Dutch patients with Pompe disease, the allele frequency of the variant was 5.5%, and evidence suggests that it is a founder variant in that population (PMID 9660056). This variant has been reported in more than 13 individuals diagnosed with Pompe disease; for at least 6 individuals, residual GAA activity is available and is in the deficient range (PMIDs 9660056, 16838077, 23430847, 23601496, 24495340, 27189384), with some patients also reported to be on enzyme replacement therapy and/or to have documentation of symptoms consistent with infantile onset Pompe disease (PMID 23402890, 23430847, 23601496, 24495340) (PP4_Moderate). More data is available in the literature but the maximum strength of evidence for PP4, as specified by the ClinGen LSD VCEP, can already be applied.. Ten of these individuals are compound heterozygous for the variant and a pathogenic variant (PMID: 9660056, 16838077, 16917947, 23402890, 23430847), phase unknown in all cases, and one is homozygous (PMID: 23601496)(PM3_Very strong). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00005 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In functional studies, when expressed in COS cells, this variant resulted in no increase in GAA activity and showed evidence of abnormal processing (PMIDs 9660056, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.963, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 188797; 2 star review status) with 8 submitters all classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved on August 17, 2021)