Submissions for variant NM_201596.3(CACNB2):c.590C>T (p.Ser197Phe)

gnomAD frequency: 0.00064  dbSNP: rs150528041

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000170864	SCV000050761	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000170864	SCV000223419	likely benign	not provided	2019-03-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26707467, 20817017, 31887354, 24055113, 23414114, 25637381, 24752249, 27711072, 25467552, 30821013, 30847666)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079387	SCV000261313	likely benign	Brugada syndrome 4	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000185499	SCV000538562	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 associated with autism; ExAC: 0.1% (60/65764) European chromosomes
Ambry Genetics	RCV000617381	SCV000736270	likely benign	Cardiovascular phenotype	2019-01-29	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185499	SCV000917104	likely benign	not specified	2018-06-18	criteria provided, single submitter	clinical testing	Variant summary: CACNB2 c.428C>T (p.Ser143Phe) results in a non-conservative amino acid change located in the Guanylate kinase/L-type calcium channel beta subunit of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 278284 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 352 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.428C>T has been reported in the literature in individuals affected with Brugada Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. In addition, there was no statistical difference in mean J-point elevation between carriers and non-carriers (Ghouse_2017), also supporting a benign outcome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 likely benign and 2 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852599	SCV000995302	likely benign	Cardiomyopathy	2019-02-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001079387	SCV001471062	likely benign	Brugada syndrome 4	2021-11-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000170864	SCV005041503	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CACNB2: BS1, BS2
CSER _CC_NCGL, University of Washington	RCV000148448	SCV000190147	uncertain significance	Brugada syndrome	2014-06-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000170864	SCV001918353	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000170864	SCV001954674	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745214	SCV005344392	likely benign	CACNB2-related disorder	2024-04-10	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).