ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5747A>G (p.Gln1916Arg) (rs186867242)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248947 SCV000318309 likely benign Cardiovascular phenotype 2017-04-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Subpopulation frequency in support of benign classification;In silico models in agreement (benign)
Ambry Genetics RCV000718466 SCV000849330 likely benign History of neurodevelopmental disorder 2017-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Invitae RCV000866145 SCV001007205 likely benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194038 SCV001363276 uncertain significance not specified 2019-02-25 criteria provided, single submitter clinical testing Variant summary: The variant, CACNA1C c.5747A>G (p.Gln1916Arg) results in a conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 277978 control chromosomes, predominantly at a frequency of 0.0029 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 290 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.5747A>G has been reported in the literature in individuals affected with sudden cardiac death, sudden unexplained death syndrome and congenital long-QT syndrome (Liu_2017, Hata_2016, Chae_2017) including one large family study that showed incomplete penetrance for the variant. However, all these studies were of the same ethnic compoisition as seen in the control databases. Therefore, these reports do not provide unequivocal evidence supporting a deleterious outcome. Electrophysiological experiments using CACNA1C-Q1916R protein showed a reduction in amplitude of the current produced by the L-type calcium channel current. Moreover, in a human ventricular cell model used to stimulate action potential of endocardium and epicardium, the variant showed a 30% reduction in the conductance of the total ICa-L and AP duration at the level of 90% repolarization was reduced by 14.29% compared to WT (Liu_2017). A ClinVar submissions from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign, however, this was submitted prior to the Liu_2017 publication. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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