ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.643G>T (p.Gly215Cys) (rs121918258)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478937 SCV000565252 likely pathogenic not provided 2016-04-20 criteria provided, single submitter clinical testing 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.
Counsyl RCV000667041 SCV000791431 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-05-10 criteria provided, single submitter clinical testing
Invitae RCV000667041 SCV000958219 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 215 of the MUT protein (p.Gly215Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous as well as in combination with another MUT variant in individuals affected with methylmalonic acidemia (PMID: 16281286, 26790480). ClinVar contains an entry for this variant (Variation ID: 418341). 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"; Align-GVGD: "Class C0"). This variant disrupts the p.Gly215 amino acid residue in MUT. Other variant(s) that disrupt this residue have been observed in individuals with MUT-related conditions (PMID: 15643616, 16281286, 16451139), 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.

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