Submissions for variant NM_022132.5(MCCC2):c.577C>T (p.Arg193Cys)

gnomAD frequency: 0.00004  dbSNP: rs547662164

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248667	SCV001422172	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 193 of the MCCC2 protein (p.Arg193Cys). This variant is present in population databases (rs547662164, gnomAD 0.006%). This missense change has been observed in individual(s) with 3MCC deficiency (PMID: 31730530; Invitae). ClinVar contains an entry for this variant (Variation ID: 203804). 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%. Experimental studies have shown that this missense change affects MCCC2 function (PMID: 11181649). This variant disrupts the p.Arg193 amino acid residue in MCCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001248667	SCV001526893	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282018	SCV002572307	pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2025-01-24	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.577C>T (p.Arg193Cys) 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 allele was found at a frequency of 7.8e-05 in 1,606,882 control chromosomes in the gnomAD database (v4.1 dataset). This frequency is not significantly higher than the maximum estimated for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.0042), allowing no conclusion about variant significance. The variant, c.577C>T, has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (e.g. Baumgartner_2001, Grunert_2012, Wang_2019, Cheng_2023, and in an internal patient (LabCorp Genetics (formerly Invitae)). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant effect resulted in <10% of normal activity (Baumgartner_2001). The following publications have been ascertained in the context of this evaluation (PMID: 22642865, 31730530, 11181649, 36822454). ClinVar contains an entry for this variant (Variation ID: 203804). Based on the evidence outlined above, the variant was classified as pathogenic.