Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000186003 | SCV000238963 | pathogenic | not provided | 2021-04-01 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25356967, 22642865, 27033733, 21071250) |
Invitae | RCV000525215 | SCV000644141 | pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 355 of the MCCC2 protein (p.Leu355Phe). This variant is present in population databases (rs757052602, gnomAD 0.3%). This missense change has been observed in individual(s) with 3-methylcrotonylglycinuria (PMID: 21071250, 25356967; Invitae). ClinVar contains an entry for this variant (Variation ID: 203806). 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%. For these reasons, this variant has been classified as Pathogenic. |
Eurofins Ntd Llc |
RCV000186003 | SCV000854812 | likely pathogenic | not provided | 2017-10-17 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000525215 | SCV002022767 | likely pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2023-07-25 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001271404 | SCV002041770 | pathogenic | Methylcrotonyl-CoA carboxylase deficiency | 2021-11-23 | criteria provided, single submitter | clinical testing | Variant summary: MCCC2 c.1065A>T (p.Leu355Phe) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251280 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.00036 vs 0.0042), allowing no conclusion about variant significance. c.1065A>T has been reported in the literature as a homozygous genotype in multiple individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency with characteristic biochemical profiles, namely, elevated excretion of 3-hydroxyisovaleric acid (3-HIVA), 3-methylcrotonylglycine (3-MCG) and also subsequently cited by others (example, Nguyen_2011, Grunert_2012, Adhikari_2020, Shepard_2015, Fonseca_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal MCC enzyme activity in a homozygous individual. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Ambry Genetics | RCV002513958 | SCV003717149 | uncertain significance | Inborn genetic diseases | 2021-07-20 | criteria provided, single submitter | clinical testing | Nguyen, 2011; Shepard, 2015; Forsyth, 2016 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
Baylor Genetics | RCV000525215 | SCV004194327 | pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2023-10-14 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV001271404 | SCV001452530 | pathogenic | Methylcrotonyl-CoA carboxylase deficiency | 2020-09-16 | no assertion criteria provided | clinical testing |