GAA p.Phe767fs

The NM_000152.5:c.2300del (p.Phe767SerfsTer14) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Western blot of protein from the cultured skin fibroblasts of a patient with this variant showed no GAA cross-reactive material i.e. CRIM-negative (PMID: 22252923), supporting that c.2300del is a loss of function variant (PVS1). This patient has <1% normal GAA activity in skin fibroblasts (PP4_Moderate) and is homozygous for the variant (PMID: 22252923, personal communication) (PM3_Supporting). A patient with Pompe disease who is heterozygous for the variant has been reported but further details are unavailable and the second variant was not reported (PMID: 18425781). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555341; 1 star review status) with one submitter classifying the variant as pathogenic and one as likely 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.