Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001339747 | SCV001533515 | uncertain significance | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2022-09-18 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 434 of the MCCC2 protein (p.Val434Leu). This variant is present in population databases (rs758506791, gnomAD 0.003%). This missense change has been observed in individual(s) with 3MCC deficiency (PMID: 22642865). ClinVar contains an entry for this variant (Variation ID: 1036699). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MCCC2 function (PMID: 22642865). 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. |
| Ce |
RCV002292631 | SCV002586056 | likely pathogenic | not provided | 2022-08-01 | criteria provided, single submitter | clinical testing | MCCC2: PM2, PM3, PP4, PS3:Supporting |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509666 | SCV002819590 | likely pathogenic | Methylcrotonyl-CoA carboxylase deficiency | 2022-12-15 | criteria provided, single submitter | clinical testing | Variant summary: MCCC2 c.1300G>C (p.Val434Leu) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251484 control chromosomes (gnomAD). c.1300G>C has been reported in the literature in homozygous individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (Grunert_2012, Navarrete_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant severely reduced protein expression. However, the resulting protein retained most of its enzymatic activity (73.7-77% residual activity, Grunert_2012). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Natera, |
RCV001339747 | SCV002084920 | uncertain significance | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2020-02-01 | no assertion criteria provided | clinical testing |