ClinVar Miner

Submissions for variant NM_020166.5(MCCC1):c.694C>T (p.Arg232Trp)

gnomAD frequency: 0.00001  dbSNP: rs727504004
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000153467 SCV000202974 uncertain significance not provided 2014-02-21 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001056550 SCV001221000 uncertain significance 3-methylcrotonyl-CoA carboxylase 1 deficiency 2022-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 232 of the MCCC1 protein (p.Arg232Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 16010683). ClinVar contains an entry for this variant (Variation ID: 167272). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences RCV003390844 SCV004119760 uncertain significance MCCC1-related disorder 2023-08-17 criteria provided, single submitter clinical testing The MCCC1 c.694C>T variant is predicted to result in the amino acid substitution p.Arg232Trp. This variant was reported in the heterozygous state in an individual with absent 3-methylcrotonyl-CoA carboxylase enzyme activity in fibroblasts. This individual was ascertained due to abnormal newborn screening results, and follow-up studies showed that this individual had largely normal development (Dantas et al. 2005. PubMed ID: 16010683; Grünert et al. 2012. PubMed ID: 22642865). This variant was also documented in a different cohort with abnormal newborn screening results (Al-Jasmi et al. 2016. PubMed ID: 26589311). At PreventionGenetics, this variant was detected in the homozygous state in an individual who had abnormal newborn screening results suggestive of 3-methylcrotonyl-CoA carboxylase deficiency (internal data). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc. RCV001056550 SCV002079112 uncertain significance 3-methylcrotonyl-CoA carboxylase 1 deficiency 2021-09-30 no assertion criteria provided clinical testing

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