ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1468G>A (p.Gly490Arg) (rs121912775)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586094 SCV000223330 likely benign not provided 2021-06-17 criteria provided, single submitter clinical testing Published functional studies demonstrate no damaging effect (Antzelevitch et al., 2007).; This variant is associated with the following publications: (PMID: 22581653, 17224476, 20301690, 20817017, 23414114, 24183960, 25333069, 26707467, 27711072, 25974115, 30027834, 30847666, 26582918, 28807990, 30821013, 27535533)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000170775 SCV000271528 benign not specified 2018-04-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV001085545 SCV000285586 likely benign Long QT syndrome 2020-11-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000586094 SCV000334437 uncertain significance not provided 2015-08-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586094 SCV000697541 likely benign not provided 2016-12-19 criteria provided, single submitter clinical testing Variant summary: The CACNA1C c.1468G>A (p.Gly490Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 53/64982 control chromosomes at a frequency of 0.0008156, which is approximately 82 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this variant is likely a benign polymorphism. This variant has been reported in one male Brugada patient with short QT (QTc=346ms) and one female HCM patient with long QT (QTc=495ms) (Antzelevitch_2007, D'Argenio_2014). In vitro study showed that the levels of calcium current in cells transfected with CACNA1C p.G490R were less than 10% of the wild-type levels. However, the causality of the decrease of calcium current to Brugada syndrome or arrhythmia is not well-established. Fluorescence assay showed that the protein trafficing was not impaired (Antzelevitch_2007). In addition, two clinical diagnostic laboratories recently classified this variant as likely benign, though other clinical diagnostic laboratories/databases classified this variant as VUS or pathogenic. Taken together, this variant is classified as likely benign.
Ambry Genetics RCV000618330 SCV000736439 benign Cardiovascular phenotype 2017-09-06 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Mendelics RCV000334098 SCV001138624 uncertain significance Timothy syndrome 2019-05-28 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256682 SCV001433055 uncertain significance Long QT syndrome 1 2020-03-02 criteria provided, single submitter clinical testing
OMIM RCV000019201 SCV000039489 pathogenic Brugada syndrome 3 2007-01-30 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058286 SCV000089806 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17224476;PMID:20817017). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneReviews RCV000019201 SCV000188929 pathogenic Brugada syndrome 3 2014-04-10 no assertion criteria provided literature only
Clinical Genetics,Academic Medical Center RCV000586094 SCV001918320 uncertain significance not provided no assertion criteria provided clinical testing

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