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

gnomAD frequency: 0.00003  dbSNP: rs374528680

Total submissions: 10

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
Labcorp Genetics (formerly Invitae), Labcorp	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	benign	Cardiovascular phenotype	2023-10-18	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 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
Molecular Genetics, Royal Melbourne Hospital	RCV000988770	SCV004812339	uncertain significance	Timothy syndrome	2023-09-04	criteria provided, single submitter	clinical testing	This sequence change in CACNA1C is predicted to replace glycine with arginine at codon 1911, p.(Gly1911Arg). The glycine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (11/19,536 alleles) in the East Asian population. This variant has been reported in multiple probands with cardiac phenotypes (PMID: 25184293, 26230511, 23861362). An in vitro functional study using Cav1.2 channel vectors expressed in HEK293T cells showed increased calcium ion production during cardiac action potential suggesting that this variant impacts protein function however limited controls were included in the assay (PMID: 25184293). Computational evidence is uninformative for the missense substitution (REVEL = 0.629). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.