Submissions for variant NM_000719.7(CACNA1C):c.5731G>C (p.Gly1911Arg)

gnomAD frequency: 0.00003  dbSNP: rs374528680

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171619	SCV000055190	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000171619	SCV000230669	uncertain significance	not provided	2015-02-02	criteria provided, single submitter	clinical testing
Invitae	RCV000226828	SCV000285599	likely benign	Long QT syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478546	SCV000611378	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2021-09-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855639	SCV000697555	uncertain significance	not specified	2019-04-29	criteria provided, single submitter	clinical testing	Variant summary: CACNA1C c.5731G>C (p.Gly1911Arg) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249708 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 56 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.5731G>C, has been reported in the literature in individuals affected with Brugada Syndrome, long QT syndrome or sudden unexplained infant death (Allegue_2015, Hennessey_2014). However, one publication, Hennessey_2014, suggests the variant is inherited from the asymptomatic father, although his DNA was not available for analysis. In electrophysiological analyses, the variant was observed to cause a gain of function of CaV1.2 suggesting increased susceptibility for arrhythmias in certain clinical settings (Hennessey_2014). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Ambry Genetics	RCV000617712	SCV000737990	uncertain significance	Cardiovascular phenotype	2021-07-22	criteria provided, single submitter	clinical testing	The p.G1911R variant (also known as c.5731G>C), located in coding exon 45 of the CACNA1C gene, results from a G to C substitution at nucleotide position 5731. The glycine at codon 1911 is replaced by arginine, an amino acid with dissimilar properties. This variant has been described in a patient with features suggestive of Timothy syndrome and in a case of sudden unexplained infant death (SUID). In the same study, functional in vitro analyses suggested this variant would lead to an increased Ca2+ influx during the cardiac action potential and a longer action potential duration, thus suggesting possible gain of function effects (Hennessey JA et al. PLoS ONE, 2014 Sep;9:e106982). In another study, this variant, reported as p.G1959R, was detected in a patient with Brugada syndrome (Allegue C et al. PLoS ONE, 2015 Jul;10:e0133037). This alteration also has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013 Aug;6:337-46). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852446	SCV000995138	uncertain significance	Cardiomyopathy	2018-02-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000988770	SCV001138627	uncertain significance	Timothy syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000171619	SCV003830333	uncertain significance	not provided	2019-12-05	criteria provided, single submitter	clinical testing