Submissions for variant NM_022132.5(MCCC2):c.1309A>G (p.Ile437Val)

gnomAD frequency: 0.00004  dbSNP: rs119103224

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000002002	SCV000644143	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 437 of the MCCC2 protein (p.Ile437Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs119103224, gnomAD 0.005%). This missense change has been observed in individual(s) with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865; 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: 1925). 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. Studies have shown that this missense change results in activation of a cryptic donor site and introduces a premature termination codon (PMID: 11181649). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000002002	SCV000915335	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2017-04-27	criteria provided, single submitter	clinical testing	The MCCC2 c.1309A>G (p.Ile437Val) variant is described in two studies in which it is found in a compound heterozygous state in one individual and in a heterozygous state in another individual, both with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (Baumgartner et al. 2001; Grünert et al. 2012). The p.Ile437Val variant was not present in 100 controls (Grünert et al. 2012) and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies using RT-PCR showed that the p.Ile437Val variant activates a cryptic splice donor site, which when used results in the deletion of the last 64 base pairs of exon 14 from the mature transcript. Direct sequencing of the RT-PCR product showed that virtually all the transcript present uses the new donor site (Baumgartner et al. 2001). Based on the evidence, the p.Ile437Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000002002	SCV004194344	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2023-09-21	criteria provided, single submitter	clinical testing
OMIM	RCV000002002	SCV000022160	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2001-02-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723531	SCV001953651	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723531	SCV001974999	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000002002	SCV002084921	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2020-07-30	no assertion criteria provided	clinical testing