Submissions for variant NM_000719.7(CACNA1C):c.5918G>A (p.Arg1973Gln)

gnomAD frequency: 0.00140  dbSNP: rs112414325

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000079305	SCV000050757	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000223757	SCV000111175	benign	not specified	2016-06-21	criteria provided, single submitter	clinical testing
Invitae	RCV001085859	SCV000285600	benign	Long QT syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000241853	SCV000319009	benign	Cardiovascular phenotype	2016-06-27	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
GeneDx	RCV000223757	SCV000512465	benign	not specified	2016-10-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079305	SCV000697556	likely benign	not provided	2016-01-25	criteria provided, single submitter	clinical testing	Variant summary: CACNA1C c.5918G>A affects a conserved nucleotide, resulting in amino acid change from Arg to Gln. 3/4 in-silico tools predict this variant to be benign. This variant is found in 433/121010 control chromosomes including the large and broad populations from ExAC at a frequency of 0.0035782, which is about 358 times greater than the maximal expected frequency of a pathogenic allele (0.00001) in this gene, suggesting this variant is benign. Five homozygotes were reported in ExAC. This variant has been reported in multiple LQTS and BrS patients without strong evidence for causality (eg. co-segregation studies). Clinical diagnostic labs have classified this variant as a VUS or likely benign before the large and diverse ExAC control cohorts were available. Taken together, this variant was classified as likely benign.
Ambry Genetics	RCV000716980	SCV000847825	benign	History of neurodevelopmental disorder	2016-06-27	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;In silico models in agreement (benign);Insufficient or conflicting evidence
CeGaT Center for Human Genetics Tuebingen	RCV000079305	SCV004033181	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CACNA1C: PM5, BP4, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003925045	SCV004745998	benign	CACNA1C-related disorder	2019-09-17	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Blueprint Genetics	RCV000157127	SCV000206850	likely benign	Short QT syndrome	2014-10-14	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223757	SCV000280058	uncertain significance	not specified	2014-12-02	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed we consider this a variant of uncertain significance. This variant is novel. Pathogenic variants in CACNA1C are associated with Timothy syndrome and Brugada syndrome. This is a semi-conservative amino acid change with a hydrophilic basic polar Arginine replaced with a hydrophilic polar Glutamine. The variant is found in a highly conserved region of the CACNA1C gene. The reporting lab observed the variant in 2 out of 353 presumably healthy individuals of mixed ethnic background. Based on these data it is currently unclear whether this variant can cause disease, however given the presence in controls for a variant in a gene thus far only associated with quite rare diseases, it seems most likely that this variant does not cause rare Mendelian disease such as long QT syndrome.
Clinical Genetics, Academic Medical Center	RCV000079305	SCV001918606	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000079305	SCV001930008	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079305	SCV001958595	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079305	SCV001972918	likely benign	not provided		no assertion criteria provided	clinical testing