The NM_000152.5:c.1054C>T (p.Gln352Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one individual with this variant identified by newborn screening had documented GAA activity in the affected range in dried blood spot and was compound heterozygous for the variant and c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu]), which has not yet been evaluated by the ClinGen Lysosomal Diseases VCEP, phase unconfirmed (PMID: 24513544). However, in the absence of clinical symptoms to support that the variant causes Pompe disease, PP4 and PM3 will not be applied. The highest population minor allele frequency in gnomAD v4.1.0. is 8.474e-7 (1/1180028 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. 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). GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 10, 2026)