Submissions for variant NM_201596.3(CACNB2):c.1776C>A (p.Asp592Glu)

gnomAD frequency: 0.00045  dbSNP: rs144182966

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000170876	SCV000050764	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
CSER _CC_NCGL, University of Washington	RCV000148451	SCV000190150	uncertain significance	Brugada syndrome	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx	RCV000185502	SCV000223431	likely benign	not specified	2017-08-11	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.
Invitae	RCV001087038	SCV000291909	likely benign	Brugada syndrome 4	2023-12-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000185502	SCV000538565	uncertain significance	not specified	2016-06-16	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: Frequency; Multiple papers classify as VUS; ClinVar: 1 LB, 2 VUS
Ambry Genetics	RCV000619292	SCV000737851	likely benign	Cardiovascular phenotype	2018-10-09	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185502	SCV003922460	likely benign	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: CACNB2 c.1614C>A (p.Asp538Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 251314 control chromosomes. The observed variant frequency is approximately 140 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 benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000170876	SCV001922668	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000185502	SCV001955928	benign	not specified		no assertion criteria provided	clinical testing