ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.2020C>G (p.Leu674Val) (rs1164271240)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000528595 SCV000641777 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-04-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 674 of the MUT protein (p.Leu674Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MUT-related disease. This variant has been observed in an individual affected with methylmalonic acidemia and very high methylmalonic acid in urine, in combination with a pathogenic variant on the opposite chromosome (Invitae). Another missense substitution affecting the same codon (p.Leu674Phe) has been reported as homozygous in an individual affected with methylmalonic acidemia (PMID: 22727635). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a missense change which is predicted to impact protein function and has been observed in combination with a pathogenic variant in an affected individual meeting a biochemical profile specific for methylmalonic acidemia. This 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.

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