Submissions for variant NM_000719.7(CACNA1C):c.6040G>A (p.Val2014Ile)

gnomAD frequency: 0.00015  dbSNP: rs199473660

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724590	SCV000223404	uncertain significance	not provided	2016-11-09	criteria provided, single submitter	clinical testing	p.Val2014Ile (GTC>ATC): c.6040 G>A in exon 46 in the CACNA1C gene (NM_000719.6). The V2014I variant was not observed with any significant frequency in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V2014I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A recent publication classifies V2014I as a variant of unknown significance (Dorschner et al., 2013). The variant is found in LQT panel(s).
Eurofins Ntd Llc (ga)	RCV000724590	SCV000230709	uncertain significance	not provided	2015-03-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212341	SCV000538550	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 4 papers in HGMD, 3 reference presence in control databases; ExAC: 0.1% (19/13788) South Asian chromosomes
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086309	SCV000562897	likely benign	Long QT syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620928	SCV000735410	benign	Cardiovascular phenotype	2022-01-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678943	SCV000805156	uncertain significance	Brugada syndrome 3	2018-03-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000988771	SCV001138628	uncertain significance	Timothy syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724590	SCV003830328	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724590	SCV005434444	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	CACNA1C: BP4
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058289	SCV000089809	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20817017). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148443	SCV000190142	uncertain significance	Brugada syndrome (shorter-than-normal QT interval)	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004734615	SCV005344734	uncertain significance	CACNA1C-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The CACNA1C c.6040G>A variant is predicted to result in the amino acid substitution p.Val2014Ile. This variant was reported in individuals with Brugada syndrome (Table1, Burashnikov et al. 2010. PubMed ID: 20817017; Risgaard et al. 2013. PubMed ID: 23414114). This variant is mainly classified as likely benign/uncertain by multiple publications (Table S1, Dorschner et al. 2013. PubMed ID: 24055113; Amendola et al. 2015. PubMed ID: 25637381; Marschall et al. 2019. PubMed ID: 31737537; Maltese et al. 2019. PubMed ID: 31539150 ) and likely pathogenic by one publication (Campuzano et al. 2019. PubMed ID: 30821013). This variant is reported in 0.082% of alleles in individuals of South Asian descent in gnomAD. In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/67556/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.