ClinVar Miner

Submissions for variant NM_020166.3(MCCC1):c.640_641delGG (p.Gly214Asnfs) (rs886058209)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000592355 SCV000704862 pathogenic not provided 2017-01-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000288396 SCV000442296 uncertain significance 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2017-04-28 criteria provided, single submitter clinical testing The MCCC1 c.640_641delGG (p.Gly214AsnfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly214AsnfsTer5 variant has been reported in two studies in which it was found in a compound heterozygous state in two siblings with isolated 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (Dantas et al. 2005; Grunert et al. 2012). Both of these individuals carried the same variant on the second allele. While both siblings had biochemical profiles of 3-MCC deficiency, they were reportedly asymptomatic at the time of the study and were lost to follow-up (Grunert et al. 2012). Control data are unavailable for the p.Gly214AsnfsTer5 variant, which is also not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of frameshift variants and limited evidence from the literature, the p.Gly214AsnfsTer5 variant is classified as a variant of unknown significance but suspicious for pathogenicity for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000288396 SCV000961203 pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2018-10-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly214Asnfs*5) 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 observed in combination with another MCCC1 variant in an individual affected with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 16010683). ClinVar contains an entry for this variant (Variation ID: 344312). 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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