ClinVar Genomic variation as it relates to human health

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

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.

This variant is associated with the following publications: (PMID: 25637381, 20817017, 24055113, 23861362, 27650965)

CACNB2: BP4, BS1, BS2

Criteria: BS1, PP3

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.

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.