Submissions for variant NM_022132.5(MCCC2):c.1433C>G (p.Ala478Gly)

gnomAD frequency: 0.00082  dbSNP: rs35068278

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723495	SCV000114040	likely pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000723495	SCV000238966	uncertain significance	not provided	2024-06-15	criteria provided, single submitter	clinical testing	Reported as heterozygous in an individual with seizures and developmental delay who also had a de novo variant in PP2D1 and a variant in SCN9A (PMID: 31847883); 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: 31847883)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539137	SCV000644145	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 478 of the MCCC2 protein (p.Ala478Gly). This variant is present in population databases (rs35068278, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with 3 Methylcrotonyl-CoA carboxylase deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 96030). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Fulgent Genetics, Fulgent Genetics	RCV000539137	SCV000895715	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000539137	SCV001318183	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509204	SCV002819800	uncertain significance	not specified	2024-08-15	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.1433C>G (p.Ala478Gly) 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 0.0014 in 1614060 control chromosomes in the gnomAD database (v4), including 5 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.0014 vs 0.0042), allowing no conclusion about variant significance. c.1433C>G has been reported in the literature in at least one individual affected with Infantile spasms and uncontrolled seizures (e.g. Salfati_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Methylcrotonyl-CoA Carboxylase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31847883). ClinVar contains an entry for this variant (Variation ID: 96030). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002513843	SCV003727466	uncertain significance	Inborn genetic diseases	2022-05-02	criteria provided, single submitter	clinical testing	The c.1433C>G (p.A478G) alteration is located in exon 15 (coding exon 15) of the MCCC2 gene. This alteration results from a C to G substitution at nucleotide position 1433, causing the alanine (A) at amino acid position 478 to be replaced by a glycine (G). Based on data from the Genome Aggregation Database (gnomAD) database, the MCCC2 c.1433C>G alteration was observed in 0.05% (145/282,790) of total alleles studied, with a frequency of 0.1% (128/129,106) in the European (non-Finnish) subpopulation. The p.A478G alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000723495	SCV004700379	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MCCC2: PM5
Natera, Inc.	RCV001271408	SCV001452534	uncertain significance	Methylcrotonyl-CoA carboxylase deficiency	2020-09-16	no assertion criteria provided	clinical testing