Submissions for variant NM_201596.3(CACNB2):c.1817G>C (p.Arg606Pro)

dbSNP: rs577739840

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001038210	SCV001201671	uncertain significance	Brugada syndrome 4	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 552 of the CACNB2 protein (p.Arg552Pro). This variant is present in population databases (rs577739840, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with sudden unexpected death (PMID: 30415094). This variant is also known as NM_000724 c.1652G>C p.R551P. ClinVar contains an entry for this variant (Variation ID: 836974). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527029	SCV001737851	likely benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: CACNB2 c.1655G>C (p.Arg552Pro) results in a non-conservative amino acid change in 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 0.00013 in 251270 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 134 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 South Asian origin. c.1655G>C has been reported in the literature in a young sudden unexplained death case (Scheiper_2018). This report however, does 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. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002400227	SCV002706023	likely benign	Cardiovascular phenotype	2022-05-10	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.
Revvity Omics, Revvity	RCV001038210	SCV003828867	uncertain significance	Brugada syndrome 4	2019-12-19	criteria provided, single submitter	clinical testing