Submissions for variant NM_022132.5(MCCC2):c.568C>T (p.His190Tyr)

gnomAD frequency: 0.00002  dbSNP: rs773774134

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000185999	SCV000231782	pathogenic	not provided	2015-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000185999	SCV000238959	pathogenic	not provided	2018-09-20	criteria provided, single submitter	clinical testing	The H190Y variant in the MCCC2 gene has been reported previously in association with 3-methylcrotonyl-CoA carboxylase deficiency, in an affected individual who was homozygous for the H190Y variant (Dantas et al., 2005). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The H190Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, and expression studies found that H190Y is associated with severely decreased 3-methylcrotonyl-CoA carboxylase activity (Dantas et al., 2005). Missense variants in the same codon (H190R) and nearby residues (R193C and R193H) have been reported in the Human Gene Mutation Database in association with 3-methylcrotonyl-CoA carboxylase deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret H190Y as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179523	SCV000823103	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 190 of the MCCC2 protein (p.His190Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs773774134, ExAC 0.001%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 16010683). ClinVar contains an entry for this variant (Variation ID: 198252). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MCCC2 function (PMID: 16010683). This variant disrupts the p.His190 amino acid residue in MCCC2. Other variant(s) that disrupt this residue have been observed in individuals with MCCC2-related conditions (PMID: 16010683, 17968484), which suggests that this may be a clinically significant amino acid residue. 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.
SIB Swiss Institute of Bioinformatics	RCV000179523	SCV000883287	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for MCC2 deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/16010683).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298507	SCV002598941	likely pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2022-09-10	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.568C>T (p.His190Tyr) results in a conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251464 control chromosomes. c.568C>T has been reported in the literature as a homozygous genotype in at-least one individual affected with a mild phenotype of Methylcrotonyl-CoA Carboxylase Deficiency (example, Dantas_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in-vitro (example, Dantas_2005). The most pronounced variant effect results in absence of normal 3-methylcrotonyl-CoA carboxylase (MCC) activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=1; P/LP, n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000179523	SCV004194354	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2023-11-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751343	SCV005354521	likely pathogenic	MCCC2-related disorder	2024-07-15	no assertion criteria provided	clinical testing	The MCCC2 c.568C>T variant is predicted to result in the amino acid substitution p.His190Tyr. This variant was reported in the homozygous state in one mildly affected individual with 3-methylcrotonyl-CoA carboxylase deficiency (Dantas et al 2005. PubMed ID: 16010683). In an in vitro expression study, the p.His190Tyr substitution was reported to abolish enzyme activity (Dantas et al 2005. PubMed ID: 16010683). An alternative substitution of the same amino acid (p.His190Arg) was reported along with a second likely pathogenic MCCC2 variant in an individual with 3-methylcrotonyl-CoA carboxylase deficiency (Uematsu et al. 2007. PubMed ID: 17968484). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.