Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Fulgent Genetics, |
RCV000534214 | SCV005666611 | likely pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2024-04-13 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004701629 | SCV005204937 | uncertain significance | not specified | 2025-05-21 | criteria provided, single submitter | clinical testing | Variant summary: MCCC2 c.995G>A (p.Arg332Gln) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 9.1e-05 in 251448 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (9.1e-05 vs 0.0042), allowing no conclusion about variant significance. c.995G>A has been observed in individual(s) affected with Methylcrotonyl-CoA Carboxylase Deficiency (example: Cook_2024, internal data). In at least one of these individuals the variant was found to be carried in trans with a pathogenic variant. These data indicate that the variant may be associated with disease. 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: 38146699). ClinVar contains an entry for this variant (Variation ID: 467811). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Gene |
RCV001559390 | SCV001781606 | uncertain significance | not provided | 2019-08-20 | criteria provided, single submitter | clinical testing | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
| Labcorp Genetics |
RCV000534214 | SCV000644156 | pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2025-01-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 332 of the MCCC2 protein (p.Arg332Gln). This variant is present in population databases (rs144203670, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of 3-methylcrotonyl-CoA carboxylase deficiency (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 467811). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MCCC2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Natera, |
RCV001271401 | SCV001452527 | uncertain significance | Methylcrotonyl-CoA carboxylase deficiency | 2020-09-16 | no assertion criteria provided | clinical testing |