ClinVar

Description

The NM_000152.5:c.2316G>T variant in GAA is a missense variant predicted to cause substitution of Tryptophan by Cysteine at amino acid 772 (p.Trp772Cys). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant and this variant has not been reported in the literature in any individuals with Pompe disease. The computational predictor REVEL gives a score of 0.942 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.2314T>C (p.Trp772Arg) (PMID: 31619483, 18757064, ClinVar ID: 552527) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 392862, 2 star review status) with 3 submitters classifying the variant as Uncertain Significance. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3, PM2_Supporting, PM5_Supporting.