ClinVar Miner

Submissions for variant NM_022132.5(MCCC2):c.1065A>T (p.Leu355Phe) (rs757052602)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186003 SCV000238963 pathogenic not provided 2018-02-09 criteria provided, single submitter clinical testing The L355F missense variant in the MCCC2 gene has been reported previously in association with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency in individuals who were homozygous for L355F or heterozygous for L355F and a second variant in MCCC2 (Nguyen et al., 2011; Shepard et al., 2014; Forsyth et al., 2016). The L355F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore we interpret L355F to be a pathogenic variant.
Invitae RCV000525215 SCV000644141 pathogenic 3-methylcrotonyl CoA carboxylase 2 deficiency 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 355 of the MCCC2 protein (p.Leu355Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs757052602, ExAC 0.3%). This variant has been reported in the literature as homozygous in individuals affected with 3-methylcrotonylglycinuria who showed low MCCC2 enzymatic activity (PMID: 21071250, 25356967, Invitae). ClinVar contains an entry for this variant (Variation ID: 203806). This variant has been observed in an individual with elevated excretion of 3-hydroxyisovaleric acid (3-HIVA), 3-methylcrotonylglycine (3-MCG), findings that are highly specific for 3-methylcrotonylglycinuria  (PMID: 21071250). 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"). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000186003 SCV000854812 likely pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing

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