ClinVar

Description

The G123D variant in the MPZ gene was identified via direct sequencing of the MPZ gene an a female patient with Déjérine-Sottas syndrome, which onset at two years of age (Braathen et al., 2010). The G123D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G123D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the extracellular domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at this residue (G123C, G123S) and in nearby residues (Y119C, D121N, N122S, T124A, T124M, T124K, C127S, C127Y) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G123D as a likely pathogenic variant.