Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002027785 | SCV002310135 | likely pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2022-01-15 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with 3MCC deficiency and/or clinical features of MCCC2-related conditions (PMID: 16010683, 19706617, 25356967). 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. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 19706617). Experimental studies have shown that this missense change affects MCCC2 function (PMID: 16010683). 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. This variant is present in population databases (rs765438239, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 352 of the MCCC2 protein (p.Gly352Arg). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003403657 | SCV004122646 | pathogenic | Methylcrotonyl-CoA carboxylase deficiency | 2023-10-09 | criteria provided, single submitter | clinical testing | Variant summary: MCCC2 c.1054G>A (p.Gly352Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Acetyl-coenzyme A carboxyltransferase, C-terminal (IPR011763) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However publications reports experimental evidence that this variant affects mRNA splicing (Dantas_2005, Stucki_2009). The variant allele was found at a frequency of 8e-06 in 251280 control chromosomes (gnomAD). c.1054G>A has been reported in the literature in individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (Dantas_2005, Shepard_2009). These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzymatic activity. The following publications have been ascertained in the context of this evaluation (PMID: 16010683, 19706617, 25356967). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV002027785 | SCV004194400 | likely pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2024-01-21 | criteria provided, single submitter | clinical testing |