Submissions for variant NM_201596.3(CACNB2):c.1206+3A>T

gnomAD frequency: 0.00005  dbSNP: rs200174877

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000243739	SCV000319496	likely benign	Cardiovascular phenotype	2022-09-21	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.
Invitae	RCV000547052	SCV000647059	uncertain significance	Brugada syndrome 4	2022-09-03	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the CACNB2 gene. It does not directly change the encoded amino acid sequence of the CACNB2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200174877, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 28600387). This variant is also known as c.1122+3A>T. ClinVar contains an entry for this variant (Variation ID: 180291). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000547052	SCV001366451	uncertain significance	Brugada syndrome 4	2019-02-15	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BS1.
GeneDx	RCV001689706	SCV001913671	uncertain significance	not provided	2020-04-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 180291; Landrum et al., 2016)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797638	SCV002041847	likely benign	not specified	2021-11-22	criteria provided, single submitter	clinical testing	Variant summary: CACNB2 c.1044+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251250 control chromosomes, predominantly at a frequency of 0.00022 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 70 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.1044+3A>T (also known as c.1122+3A>T) has been reported in the literature in at least one individual who was a cardiac arrest survivor (Mellor_2017). This individual also had a second variant for this gene c.1558G>A and authors classified both variants as VUS. This report 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Blueprint Genetics	RCV000157132	SCV000206855	uncertain significance	Cardiac arrest	2014-09-18	no assertion criteria provided	clinical testing