Submissions for variant NM_022132.5(MCCC2):c.518C>G (p.Ser173Trp)

dbSNP: rs752866557

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179522	SCV000231781	uncertain significance	not provided	2014-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235101	SCV003934005	uncertain significance	not specified	2023-05-17	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.518C>G (p.Ser173Trp) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.518C>G in individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency and no experimental evidence demonstrating an impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32778825). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003600364	SCV004446622	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2023-09-12	criteria provided, single submitter	clinical testing	This variant disrupts the p.Ser173 amino acid residue in MCCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11181649, 22642865). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 198251). This missense change has been observed in individual(s) with clinical features of 3-methylcrotonyl-CoA carboxylase deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the MCCC2 protein (p.Ser173Trp). 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.