ClinVar Genomic variation as it relates to human health

Experimental studies have shown that this missense change affects MPV17 function (PMID: 16582910). This variant disrupts the p.Arg50 amino acid residue in MPV17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16582910, 16909392). 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. 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 MPV17 protein function. ClinVar contains an entry for this variant (Variation ID: 16162). This missense change has been observed in individual(s) with clinical features of MPV17-related conditions (PMID: 16582910, 17694548, 25016221). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121909723, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 50 of the MPV17 protein (p.Arg50Trp).

The R50W pathogenic variant in the MPV17 gene has been reported previously in multiple individuals with clinical features consistent with hepatocerebral mitochondrial DNA depletion syndrome in the homozygous state, as well as in the heterozygous state in the presence of a second MPV17 variant (Spinazzola et al., 2006; Wong et al., 2007; Vilarinho et al., 2014). Additionally, functional studies in yeast with the R50W variant show that this variant impacts the function of the protein (Spinazzola et al., 2006). The R50W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R50W 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 that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R50W as a pathogenic variant.