Submissions for variant NM_022132.5(MCCC2):c.641G>C (p.Gly214Ala)

gnomAD frequency: 0.00005  dbSNP: rs277995

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000805067	SCV000945010	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 214 of the MCCC2 protein (p.Gly214Ala). This variant is present in population databases (rs277995, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 27601257; Invitae). ClinVar contains an entry for this variant (Variation ID: 650003). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001546546	SCV001766078	likely pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 27601257)
Baylor Genetics	RCV000805067	SCV004194334	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2023-10-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003928278	SCV004747081	likely pathogenic	MCCC2-related condition	2024-02-10	criteria provided, single submitter	clinical testing	The MCCC2 c.641G>C variant is predicted to result in the amino acid substitution p.Gly214Ala. This variant has been reported along with a second MCCC2 variant in several individuals with abnormal newborn screening results suggestive of 3-methylcrotonyl-CoA carboxylase (MCC) deficiency (Fonseca et al. 2016. PubMed ID: 27601257; Martín-Rivada et al. 2022. PubMed ID: 35281663). This variant has also been reported in a large cohort study of individuals with a positive newborn screening result for an inborn error of metabolism (Table S5 in Adhikari et al. 2020. PubMed ID: 32778825). This variant was found homozygous in two affected siblings (Internal Data, PreventionGenetics). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given this, the variant is interpreted as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987709	SCV004803764	likely pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2024-01-25	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.641G>C (p.Gly214Ala) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal (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 2.8e-05 in 251414 control chromosomes. c.641G>C has been reported in the literature in at-least four individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency through newborn screenings (example, Adhikari_2020, Fonseca_2016, Navarrete_2019). 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: 32778825, 27601257, 30626930). ClinVar contains an entry for this variant (Variation ID: 650003). Based on the evidence outlined above, the variant was classified as likely pathogenic.