ClinVar Genomic variation as it relates to human health

The G215C variant has been previously reported in two individuals with methylmalonic acidemia (MMA), one homozygous and one compound heterozygote (Worgan et al., 2006). The G215C 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (Q218H, N219Y, and N219D) have been reported in the Human Gene Mutation Database in association with methylmalonic aciduria (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. However, this result could also be seen if the patient had one allele with the G215C variant and one allele that was partially missing or refractory to amplification.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly215 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15643616, 16281286, 16451139). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 MUT protein function. ClinVar contains an entry for this variant (Variation ID: 418341). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 16281286, 26790480). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 215 of the MUT protein (p.Gly215Cys).

The MMUT c.643G>T varianthas been observed to be homozygous as well as in combination with another MMUT variant in individuals affected with methylmalonic acidemia (Worgan et. al., 2006; Harrington et. al., 2016). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; AlignGVGD: Class C0). The p.Gly215Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid change p.Gly215Cys in MMUT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant disrupts the p.Gly215 amino acid residue in MMUT. Other variant(s) that disrupt this residue have been observed in individuals with MMUT-related conditions (Acquaviva et. al., 2005; Worgan et. al., 2006), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.