ClinVar

Description

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 766 of the GAA protein (p.Tyr766Asn). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed on the same chromosome as p.Pro522Ser in individual(s) with Pompe disease (PMID: 31086307). ClinVar contains an entry for this variant (Variation ID: 1005758). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. This variant disrupts the p.Tyr766 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22521436, 22538254, 28394184). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.