Submissions for variant NM_020166.5(MCCC1):c.388G>A (p.Gly130Ser)

gnomAD frequency: 0.00002  dbSNP: rs202197951

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000685415	SCV000442300	uncertain significance	3-methylcrotonyl-CoA carboxylase 1 deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685415	SCV000812894	uncertain significance	3-methylcrotonyl-CoA carboxylase 1 deficiency	2023-04-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the MCCC1 protein (p.Gly130Ser). This variant is present in population databases (rs202197951, gnomAD 0.007%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 27601257, 31730530). ClinVar contains an entry for this variant (Variation ID: 344315). 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 MCCC1 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330650	SCV004039006	uncertain significance	not specified	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: MCCC1 c.388G>A (p.Gly130Ser) results in a non-conservative amino acid change located in the Biotin carboxylase-like, N-terminal domain (IPR005481) 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 1.2e-05 in 251026 control chromosomes. c.388G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (e.g. Fonseca_2016, Wang_2019, Wang_2019, Yang_2019). These data indicate that the variant may 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: 27601257, 31737040, 31730530, 30838026). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003418068	SCV004109328	uncertain significance	MCCC1-related disorder	2023-02-19	criteria provided, single submitter	clinical testing	The MCCC1 c.388G>A variant is predicted to result in the amino acid substitution p.Gly130Ser. This variant has been reported in the homozygous state or heterozygous state with a second MCCC1 variant in two asymptomatic individuals with 3-methylcrotonyl-CoA carboxylase deficiency, identified by newborn screening (Fonseca et al. 2016. PubMed ID: 27601257; Wang et al. 2019. PubMed ID: 31730530). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-182790257-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Fulgent Genetics, Fulgent Genetics	RCV000685415	SCV005661968	likely pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2024-06-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000685415	SCV002079121	uncertain significance	3-methylcrotonyl-CoA carboxylase 1 deficiency	2020-12-21	no assertion criteria provided	clinical testing