The NM_000152.5:c.1961C>A (p.Ser654Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14 out of a total of 20 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individual with Pompe disease. However, there is a ClinVar entry for this variant (Variation ID 372968), and a different variant resulting in a stop codon at the same position, c.1961C>G (p.Ser654Ter), has been reported (PMID: 31342611). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, April 9, 2026).