Submissions for variant NM_022132.5(MCCC2):c.1690T>C (p.Ter564Gln)

gnomAD frequency: 0.00004  dbSNP: rs751970792

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691743	SCV000819533	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change disrupts the translational stop signal of the MCCC2 mRNA. It is expected to extend the length of the MCCC2 protein by 3 additional amino acid residues. This variant is present in population databases (rs751970792, gnomAD 0.007%). This protein extension has been observed in individual(s) with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 16010683, 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: 570791). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000691743	SCV000916110	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2018-11-06	criteria provided, single submitter	clinical testing	The MCCC2 c.1690T>C (p.Ter564GlnextTer3) variant is a stop-lost variant that has been reported in three studies and was found in at least three individuals with 3-MCC deficiency (Dantas et al. 2005; Stadler et al. 2006; Grünert et al. 2012). One of the individuals was compound heterozygous, and two were found to be heterozygous via genomic PCR, with no detectable RNA for the second allele. Control data are unavailable for the p.Ter564GlnextTer3 variant, which is reported at a frequency of 0.000072 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of stop-lost variants, the p.Ter564GlnextTer3 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323691	SCV004029650	uncertain significance	not specified	2023-07-06	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.1690T>C (p.X564GlnextX3) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. MCCC2 c.1690T>C (p.X564GlnextX3) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 2.8e-05 in 251414 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1690T>C has been reported in the literature in an individual affected with Methylcrotonyl-CoA Carboxylase Deficiency (example: Dantas_2005). This report does 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: 16010683). 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 uncertain significance.
Natera, Inc.	RCV001271415	SCV001452541	uncertain significance	Methylcrotonyl-CoA carboxylase deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751665	SCV005360469	uncertain significance	MCCC2-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The MCCC2 c.1690T>C variant is predicted to result in extension of the open reading frame (p.*564Glnext*3). This variant is predicted to abolish the stop codon and lead to the extension of the protein by 3 amino acids (p.*564Glnext*3). This variant has been reported in the heterozygous state in two patients. A second variant was not identified in the MCCC2 gene of either patient, though no RNA was identified from the second allele in one of the patients, suggesting the presence of an additional variant not detectable via the methodology used by the researchers (Dantas et al. 2005. PubMed ID: 16010683; Grünert et al. 2012. PubMed ID: 22642865). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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.