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

gnomAD frequency: 0.00036  dbSNP: rs121912775

Total submissions: 14

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, Mass General Brigham Personalized Medicine	RCV000170775	SCV000271528	benign	not specified	2018-04-09	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085545	SCV000285586	likely benign	Long QT syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	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	RCV000170775	SCV000697541	likely benign	not specified	2023-10-12	criteria provided, single submitter	clinical testing	Variant summary: CACNA1C c.1468G>A (p.Gly490Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 231558 control chromosomes (gnomAD). The observed variant frequency is approximately 67 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 benign. This variant has been reported in individuals affected with Brugada syndrome, hypertrophic cardiomyopathy, and early repolarization syndrome, without strong evidence for causality (examples: Antzelevitch_2007, D'Argenio_2014, Chen_2021). Published functional studies demonstrate no damaging effect from this variant (Antzelevitch et al., 2007). The following publications have been ascertained in the context of this evaluation (PMID: 17224476, 24183960, 34222376). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000618330	SCV000736439	benign	Cardiovascular phenotype	2017-09-06	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.
Mendelics	RCV000334098	SCV001138624	benign	Timothy syndrome	2023-08-22	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	not provided	Brugada syndrome 3		no assertion provided	literature only
Clinical Genetics, Academic Medical Center	RCV000586094	SCV001918320	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586094	SCV001968452	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944830	SCV004766319	likely benign	CACNA1C-related disorder	2024-02-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).