Submissions for variant NM_201596.3(CACNB2):c.641G>C (p.Ser214Thr)

gnomAD frequency: 0.00078  dbSNP: rs149253719

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000170855	SCV000050760	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000170855	SCV000223410	likely benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 20817017, 24055113, 23861362, 27650965)
Invitae	RCV000988334	SCV000261732	likely benign	Brugada syndrome 4	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000185497	SCV000538563	uncertain significance	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only 1 proband in HGMD, ExAC: 0.1% (23/16008) South Asian chromosomes
Ambry Genetics	RCV000619766	SCV000735427	likely benign	Cardiovascular phenotype	2018-01-09	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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852600	SCV000995303	likely benign	Brugada syndrome	2018-02-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000988334	SCV001138009	benign	Brugada syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000170855	SCV001147837	benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CACNB2: BP4, BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185497	SCV001442722	likely benign	not specified	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: CACNB2 c.479G>C (p.Ser160Thr) results in a conservative amino acid change located in the SH3 domain (IPR001452) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 250611 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 480 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNB2 causing Brugada Syndrome phenotype (3.1e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.479G>C has been reported in the literature in individuals affected with early repolarization syndrome, Brugada Syndrome and Sudden cardiac death (Burashnikov_2010, Crotti_2012, Christiansen_2016). These reports do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x), likely benign (4x) and benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Dept of Medical Biology, Uskudar University	RCV003318351	SCV004022017	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, PP3
CSER _CC_NCGL, University of Washington	RCV000148449	SCV000190148	uncertain significance	Early repolarization associated with ventricular fibrillation	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000185497	SCV000280060	uncertain significance	not specified	2014-06-10	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. Given the lack of case data, the location and presence in general population (reviewed below) we consider this a variant of uncertain significance, probably benign. The variant is novel. This variant is in an alternative transcript where no disease-causing variants have been reported to date, according to HGMD. In total the variant has been seen in 18 of 8,254 individuals from publicly available general population datasets. The variant was reported online in 10 of 4300 Caucasian individuals and 1 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of June 10th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that cardiomyopathy variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It is listed in dbSNP (rs149253719), with data from NHLBI ESP, 1000 genomes, and ClinSeq. It looks like it was seen in 1 of 662 individuals in ClinSeq. It was observed in 6 of 1089 individuals in phase 1 of 1000 genomes including 2 of 85 American Caucasians, 2 of 93 Finnish, and 2 of 98 Italians.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000988334	SCV001192588	uncertain significance	Brugada syndrome 4	2019-06-25	no assertion criteria provided	clinical testing