ClinVar Miner

Submissions for variant NM_020166.5(MCCC1):c.1191_1192TG[1] (p.Val398fs) (rs796051985)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185993 SCV000238952 pathogenic not provided 2014-06-12 criteria provided, single submitter clinical testing The c.1193_1194delTG mutation in the MCCC1 gene has been reported previously in association with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (Grunert et al., 2012). The deletion causes a frameshift starting with codon Valine 398, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Val398GlyfsX19. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Large deletions of one or more exons of the MCCC1 gene have been reported in association with 3-MCC deficiency (Eminoglu, FT et al., 2009; Wang et al., 2012). However, at this time the data is not sufficient to estimate the frequency of such mutations in MCCC1. In two separate studies of patients with a biochemically and/or enzymatically confirmed diagnosis of 3-MCC deficiency, two mutations were identified in either the MCCC1 or MCCC2 gene in 28/28 individuals (Stadler et al., 2006; Dantas et al., 2005). In another study, mutation analysis of both genes in 83 patients identified two mutations in 76 individuals; a single mutation was identified in the remaining patients (Grunert et al., 2012). The variant is found in MCCC1 panel(s).
Invitae RCV000687710 SCV000815295 pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2018-04-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val398Glyfs*19) in the MCCC1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous in an individual affected with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865). ClinVar contains an entry for this variant (Variation ID: 203798). Loss-of-function variants in MCCC1 are known to be pathogenic (PMID: 11181649, 15359379, 22642865). For these reasons, this variant has been classified as Pathogenic.

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