ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 175 of the PMPCB protein (p.Arg175Cys). This variant is present in population databases (rs145596167, gnomAD 0.006%). This missense change has been observed in individuals with multiple mitochondrial dysfunctions syndrome (PMID: 29576218; Invitae). ClinVar contains an entry for this variant (Variation ID: 523138). 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 PMPCB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMPCB function (PMID: 29576218). This variant disrupts the p.Arg175 amino acid residue in PMPCB. Other variant(s) that disrupt this residue have been observed in individuals with PMPCB-related conditions (PMID: 29576218), which suggests that this may be a clinically significant amino acid residue. 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.