ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5731G>C (p.Gly1911Arg) (rs374528680)

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Total submissions: 8
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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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000171619 SCV000230669 uncertain significance not provided 2015-02-02 criteria provided, single submitter clinical testing
Invitae RCV000226828 SCV000285599 uncertain significance Long QT syndrome 2019-09-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1911 of the CACNA1C protein (p.Gly1911Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs374528680, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811) This variant has been reported in the literature in an individual affected with Timothy syndrome, an infant with sudden unexplained death at the age of 1 month, and in an adult with aborted cardiac arrest and a Brugada pattern on ECG (PMID: 25184293, 26230511). This variant is also described as c.5875G>C (p.Gly1959Arg) in the literature. ClinVar contains an entry for this variant (Variation ID: 191427). Experimental studies have shown that this missense change produces a gain of function of the channel by decreasing its voltage dependent inactivation (PMID: 25184293). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000515185 SCV000611378 uncertain significance Timothy syndrome; Brugada syndrome 3 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2018-09-30 criteria provided, single submitter clinical testing Insufficient evidence
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

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