ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1115T>C (p.Ile372Thr) (rs150968643)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726418 SCV000344506 uncertain significance not provided 2016-08-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000706536 SCV000463871 uncertain significance Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000726418 SCV000617963 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing The I372T variant in the MUT gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I372T variant is observed in 16/10,140 (0.15%) alleles from individuals of Ashkenazi Jewish background in the ExAC dataset (Lek et al., 2016). The I372T variant is a non-conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (V368D, R369C, R369H, T370P, A377E) have been reported in the Human Gene Mutation Database in association with methylmalonic acidemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret I372T as a variant of uncertain significance.
Invitae RCV000706536 SCV000835593 uncertain significance Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-05-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 372 of the MUT protein (p.Ile372Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs150968643, ExAC 0.07%). This variant has not been reported in the literature in individuals with MUT-related disease. ClinVar contains an entry for this variant (Variation ID: 290030). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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