ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.2020C>T (p.Leu674Phe) (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 RCV000707565 SCV000836666 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 674 of the MUT protein (p.Leu674Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous state in an individual affected with methylmalonic acidemia (PMID: 22727635). 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: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Leu674Val) has been determined to be likely pathogenic (Invitae). This suggests that the leucine residue is critical for MUT protein function and that other missense substitutions at this position may also be deleterious. In summary, the currently available 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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