ClinVar Miner

Submissions for variant NM_022132.5(MCCC2):c.693C>G (p.Ile231Met)

dbSNP: rs991996366
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001991917 SCV002277599 likely pathogenic 3-methylcrotonyl-CoA carboxylase 2 deficiency 2024-04-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 231 of the MCCC2 protein (p.Ile231Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MCCC2-related conditions (PMID: 32778825). ClinVar contains an entry for this variant (Variation ID: 1496516). 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 MCCC2 protein function with a positive predictive value of 80%. This variant disrupts the p.Ile231 amino acid residue in MCCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26589311, 29767664). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526170 SCV005040086 uncertain significance not specified 2024-03-28 criteria provided, single submitter clinical testing Variant summary: MCCC2 c.693C>G (p.Ile231Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.693C>G has been reported in the literature in an individual affected with an Inborn error of metabolism (Adhikari_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32778825). ClinVar contains an entry for this variant (Variation ID: 1496516). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV001991917 SCV005666606 likely pathogenic 3-methylcrotonyl-CoA carboxylase 2 deficiency 2024-03-31 criteria provided, single submitter clinical testing

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