The NM_000152.5:c.1216G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 406 (p.Asp406Asn). At least 2 patients with this variant have been reported to have Pompe disease. The patients were siblings from the same family and were both reported to have symptoms consistent with Pompe disease. One of the siblings had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PMID: 31966564, 31439017) (PP4_Moderate). Both siblings were compound heterozygous for the variant and c.1935C>A (p.Asp645Glu), which is classified as pathogenic by the ClinGen LD VCEP, confirmed in trans by parental testing (PMID: 31966564, 31439017) (PM3). This variant has also been reported in one case identified as affected by newborn screening, but GAA enzyme activity and clinical information were not provided (PMID: 23430949). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.81 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: 552776). 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): PM2_Supporting, PM3, PP3, PP4_Moderate (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, June 17, 2025)