Submissions for variant NM_022132.5(MCCC2):c.1322T>C (p.Ile441Thr)

gnomAD frequency: 0.00137  dbSNP: rs139852818

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186005	SCV000238965	uncertain significance	not provided	2024-09-06	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: 25087612, 20818383, 26764160, 20818363, 35281663, 30626930, 27601257)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477880	SCV000822430	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 441 of the MCCC2 protein (p.Ile441Thr). This variant is present in population databases (rs139852818, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with 3-methycrotonyl-CoA carboxylase deficiency and mitochondrial complex I deficiency (PMID: 20818383, 26764160, 27601257). ClinVar contains an entry for this variant (Variation ID: 203808). 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 not 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.
Fulgent Genetics, Fulgent Genetics	RCV000477880	SCV000895714	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2022-05-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000477880	SCV001318182	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282019	SCV002570935	uncertain significance	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.1322T>C (p.Ile441Thr) results in a non-conservative amino acid change located in the acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) 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 0.001 in 252008 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.001 vs 0.0042), allowing no conclusion about variant significance. c.1322T>C has been reported in the literature in individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (e.g. Fonseca_2016, Martin-Rivada_2022) and in an individual with mitochondrial complex I deficiency (Calvo_2010). These data do not allow any conclusion about variant significance. 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: 20818383, 26764160, 27601257, 35281663). ClinVar contains an entry for this variant (Variation ID: 203808). Based on the evidence outlined above, the variant was classified as uncertain significance.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477880	SCV000536758	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2016-03-17	no assertion criteria provided	research
Natera, Inc.	RCV001271407	SCV001452533	uncertain significance	Methylcrotonyl-CoA carboxylase deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751354	SCV005345419	uncertain significance	MCCC2-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The MCCC2 c.1322T>C variant is predicted to result in the amino acid substitution p.Ile441Thr. This variant was reported in at least three individuals with newborn screening/biochemical test results suggestive of 3-methylcrotonyl-CoA carboxylase 2 deficiency (Fonseca et al. 2016. PubMed ID: 27601257; P44 in Table S2 in Navarrete et al. 2019. PubMed ID: 30626930; Martín-Rivada Á et al. 2022. PubMed ID: 35281663). However, this variant is reported in 0.15% of alleles in individuals of Latino descent in gnomAD, which is relatively high for a pathogenic variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.