The NM_000152.5:c.1602_1605delinsAGG (p.Asn535GlyfsTer43) variant in GAA is a frameshift variant predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It has been reported in one patient who was diagnosed with infantile onset Pompe disease "based on clinical presentations and GAA enzyme activity assay" and who is compound heterozygous for the variant and c.796C>T (p.Pro266Ser). The allelic data from this patient was used in the classification of the missense change and is not included here to avoid circular logic. There is insufficient data to apply PP4. There is no ClinVar entry for this variant. 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 LSD VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 2022.