ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 287 of the GMPPB protein (p.Arg287Gln). This variant is present in population databases (rs202160208, gnomAD 0.5%). This missense change has been observed in individual(s) with congenital muscular dystrophy-dystroglycanopathy and congenital myasthenic syndrome (PMID: 24780531, 26133662). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60545). 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 not expected to disrupt GMPPB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GMPPB function (PMID: 23768512). This variant disrupts the p.Arg287 amino acid residue in GMPPB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27766311, 27874200, 28478914). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.