ClinVar Miner

Submissions for variant NM_020166.5(MCCC1):c.196C>T (p.Arg66Cys) (rs754460336)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000653493 SCV000775373 likely pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 66 of the MCCC1 protein (p.Arg66Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs754460336, ExAC 0.02%). This variant has been observed in combination with other MCCC1 variants in individuals affected with 3-methylcrotonyl-CoA carboxylase deficiency (Invitae). In one of these individuals, the variant occurs with a pathogenic variant (p.Asn560Lysfs*10) in MCCC1 and family studies indicate these two variants are on opposite chromosomes (in trans), which suggests the c.196C>T substitution may contribute to disease. ClinVar contains an entry for this variant (Variation ID: 542949). 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"). 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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