ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618330 SCV000736439 benign Cardiovascular phenotype 2017-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586094 SCV000334437 uncertain significance not provided 2015-08-26 criteria provided, single submitter clinical testing
GeneDx RCV000170775 SCV000223330 uncertain significance not specified 2017-05-18 criteria provided, single submitter clinical testing p.Gly490Arg (GGG>AGG): c.1468 G>A in exon 10 of the CACNA1C gene (NM_000719.6). The Gly490Arg variant in the CACNA1C gene has been reported in one male patient with atrial fibrillation and ST segment elevation in V1 and V2, indicative of Brugada syndrome (Antzelevitch et al., 2007). This patient's two daughters were also found to carry the Gly490Arg variant with borderline short QT intervals, but neither had inducible ST segment elevation. The same study reports Gly490Arg was not detected in 640 healthy control alleles. Antzelevitch et al. also reported the Gly490Arg variant is located between the domain I and II region of the protein, and this variant reduced the calcium channel current without altering the voltage output. Confocal microscopy failed to show abnormal protein trafficking in channels containing the Gly490Arg variant as compared to other mutant and the normal protein (Antzelevitch et al., 2007). Therefore, this report does not provide convincing evidence that Gly490Arg is unequivocally pathogenic. Furthermore, no other disease- causing mutations have been reported in surrounding residues of the CACNA1C protein, indicating this region may be tolerant of change. The NHLBI ESP Exome Variant Server reports Gly490Arg was observed in 5/8350 (0.06%) alleles from individuals of European background, indicating it may be a rare benign variant in this population. With the clinical and molecular information available at this time, we cannot definitively determine if Gly490Arg is a disease-causing mutation or a rare benign variant. The variant is found in LQT,BRUGADA panel(s).
GeneReviews RCV000019201 SCV000188929 pathogenic Brugada syndrome 3 2014-04-10 no assertion criteria provided literature only
Illumina Clinical Services Laboratory,Illumina RCV000334098 SCV000377782 likely benign Timothy syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000058286 SCV000377783 likely benign Brugada syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000231239 SCV000285586 likely benign Long QT syndrome 2017-12-12 criteria provided, single submitter clinical testing
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
OMIM RCV000019201 SCV000039489 pathogenic Brugada syndrome 3 2007-01-30 no assertion criteria provided literature only

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