Submissions for variant NM_022132.5(MCCC2):c.1423G>A (p.Gly475Arg)

gnomAD frequency: 0.00015  dbSNP: rs148773718

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533421	SCV000644144	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 475 of the MCCC2 protein (p.Gly475Arg). This variant is present in population databases (rs148773718, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865, 27601257, 30626930; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 467803). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 22642865). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000533421	SCV000916109	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2017-08-15	criteria provided, single submitter	clinical testing	The MCCC2 c.1423G>A (p.Gly475Arg) missense variant has been reported in two studies and in three individuals with 3-MCC deficiency, including one in a homozygous state and two in a compound heterozygous state (Grünert et al. 2012; Fonseca et al. 2016). The three individuals were asymptomatic and identified by newborn screening. The p.Gly475Arg variant was absent from 100 controls and is reported at a frequency of 0.00079 in the Ashkenazi Jewish population of the Genome Aggregation Database. Expression of wild type and variant p.Gly475Arg in MCCC1/MCCC2 deficient fibroblasts revealed that the variant p.Gly475Arg protein is expressed at a level similar to wild type but has 43.8%-48.5% residual MCC activity compared to wild type (Grünert et al. 2012). Based on the evidence, the p.Gly475Arg variant is classified as likely pathogenic for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000533421	SCV001448841	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2019-05-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226322	SCV002511872	likely pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2023-03-18	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.1423G>A (p.Gly475Arg) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) 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 9.5e-05 in 251378 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (9.5e-05 vs 0.0042), allowing no conclusion about variant significance. c.1423G>A has been reported in the literature in compound heterozygous individuals and at least one homozygous individual affected with Methylcrotonyl-CoA Carboxylase Deficiency (e.g. Navarrete_2019, Barbosa-Gouveia_2021). These data indicate that the variant is likely to be associated with disease. At least one functional study showed this variant results in decreased MCC activity in transfected cells compared with WT (Grunert_2012). Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002469192	SCV002765183	likely pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing	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: 22642865, 27601257, 30626930, 32778825, 35281663, 34440436)
Ambry Genetics	RCV002526154	SCV003746143	likely pathogenic	Inborn genetic diseases	2022-05-29	criteria provided, single submitter	clinical testing	The c.1423G>A (p.G475R) alteration is located in exon 15 (coding exon 15) of the MCCC2 gene. This alteration results from a G to A substitution at nucleotide position 1423, causing the glycine (G) at amino acid position 475 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (27/282790) total alleles studied. The highest observed frequency was 0.08% (8/10368) of Ashkenazi Jewish alleles. This alteration has been detected in the homozygous state as well as compound heterozygous with other pathogenic MCCC2 alterations in multiple unrelated individuals with 3-methylcrotonyl-CoA carboxylase deficiency (Grunert, 2012; Fonseca, 2016; Boemer, 2017; Navarrette, 2019; Martin-Rivada, 2022). This amino acid position is highly conserved in available vertebrate species. Functional studies showed that p.G475R is not sufficient to rescue MCC deficiency in two different MCC-deficient fibroblast cell lines (Grunert, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV000533421	SCV004194337	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-03-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000533421	SCV005666624	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-06-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915571	SCV004737013	likely pathogenic	MCCC2-related disorder	2024-02-09	no assertion criteria provided	clinical testing	The MCCC2 c.1423G>A variant is predicted to result in the amino acid substitution p.Gly475Arg. This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with MCC deficiency (Grünert et al. 2012. PubMed ID: 22642865; Fonseca et al. 2016. PubMed ID: 27601257; Navarrete et al. 2019. PubMed ID: 30626930; Barbosa-Gouveia et al. 2021. PubMed ID: 34440436). In vitro experimental studies have shown this variant leads to moderately reduced MCC activity (43.8-48.5%) relative to WT (Grünert et al. 2012. PubMed ID: 22642865). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic.