Submissions for variant NM_000719.7(CACNA1C):c.5593G>A (p.Glu1865Lys)

gnomAD frequency: 0.00012  dbSNP: rs200231105

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171801	SCV000050810	benign	not specified	2013-06-24	criteria provided, single submitter	research
CSER _CC_NCGL, University of Washington	RCV000211440	SCV000212194	uncertain significance	Brugada syndrome	2015-03-11	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003333962	SCV000602905	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617504	SCV000735311	likely benign	Cardiovascular phenotype	2018-11-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631698	SCV000752782	uncertain significance	Long QT syndrome	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1865 of the CACNA1C protein (p.Glu1865Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of CACNA1C-related conditions (PMID: 32145446). This variant is also known as c.5617G>A (p.E1873K). ClinVar contains an entry for this variant (Variation ID: 191566). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852665	SCV000995372	likely benign	Hypertrophic cardiomyopathy	2018-12-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003333962	SCV001148538	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	CACNA1C: BP4
Clinical Genetics, Academic Medical Center	RCV000171801	SCV001925167	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000171801	SCV001952075	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171801	SCV001971364	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734770	SCV005350830	uncertain significance	CACNA1C-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The CACNA1C c.5593G>A variant is predicted to result in the amino acid substitution p.Glu1865Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.