Submissions for variant NM_022132.5(MCCC2):c.416C>T (p.Thr139Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002640731	SCV003525724	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2022-03-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 139 of the MCCC2 protein (p.Thr139Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 25382614, 31730530). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700980	SCV005202918	likely pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2024-07-23	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.416C>T (p.Thr139Ile) 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 251482 control chromosomes. c.416C>T has been reported in the literature in the compound heterozygous state in individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (e.g. Wang_2019, Yang_2015, Cheng_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36822454, 31730530, 25382614). ClinVar contains an entry for this variant (Variation ID: 2203656). Based on the evidence outlined above, the variant was classified as likely pathogenic.