ClinVar Miner

Submissions for variant NM_020166.5(MCCC1):c.1330C>T (p.Arg444Cys)

gnomAD frequency: 0.00001  dbSNP: rs375996272
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493467 SCV000581988 uncertain significance not provided 2020-09-14 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a single heterozygous variant in an individual with MCC deficiency; detailed clinical information not provided (Tolve et al., 2016)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222532 SCV002500817 uncertain significance not specified 2022-03-31 criteria provided, single submitter clinical testing
Invitae RCV001834597 SCV003025201 likely pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2023-08-01 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Arg444 amino acid residue in MCCC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25382614, 26566957). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MCCC1 protein function. ClinVar contains an entry for this variant (Variation ID: 429421). This variant has not been reported in the literature in individuals affected with MCCC1-related conditions. This variant is present in population databases (rs375996272, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 444 of the MCCC1 protein (p.Arg444Cys).
Natera, Inc. RCV001834597 SCV002079097 uncertain significance 3-methylcrotonyl-CoA carboxylase 1 deficiency 2020-08-13 no assertion criteria provided clinical testing

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