The NM_000152.5:c.2655_2656del (p.Val886GlufsTer2) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two siblings with this variant and late-onset Pompe disease have been reported with GAA activity in dried blood spots below the normal range, and both are on enzyme replacement therapy (PMID 31392188, personal communication)(PP4_Moderate). These individuals are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 597005; 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.