Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000700140 | SCV000828884 | pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 230 of the MCCC2 protein (p.Asn230Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 27601257). ClinVar contains an entry for this variant (Variation ID: 577397). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCCC2 protein function. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001824869 | SCV002074349 | pathogenic | Methylcrotonyl-CoA carboxylase deficiency | 2022-01-19 | criteria provided, single submitter | clinical testing | Variant summary: MCCC2 c.688A>G (p.Asn230Asp) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes. c.688A>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple asymptomatic newborns and at-least one asymptomatic mother affected with Methylcrotonyl-CoA Carboxylase Deficiency, supported by elevated 3- hydroxyisovalerylcarnitine (C5-OH) levels above the established screening cutoff of >/= 1 micromol/L (example, Fonseca_2016). At-least two of these individuals also had supportive biochemical phenotype of elevated 3-hydroxyisovaleric acid (3-HIVA) and 3-methylcrotonylglycine (3-MCG) levels. Patients with 3-MCC deficiency experience normal growth and development until the emergence of an acute episode of metabolic decompensation, occurring typically between 6 months and 3 to 5 years of age (example, Sweetman, 2001). This episode is usually triggered by an infection or the introduction of high protein foods in the diet. Therefore, these newborn screening data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000700140 | SCV004194324 | likely pathogenic | 3-methylcrotonyl-CoA carboxylase 2 deficiency | 2023-10-22 | criteria provided, single submitter | clinical testing |