Submissions for variant NM_201596.3(CACNB2):c.380C>T (p.Ala127Val)

gnomAD frequency: 0.00022  dbSNP: rs200367454

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000245027	SCV000318131	likely benign	Cardiovascular phenotype	2022-10-07	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.
GeneDx	RCV000766681	SCV000512473	uncertain significance	not provided	2023-02-15	criteria provided, single submitter	clinical testing	Reported in one individual with idiopathic ventricular fibrillation (Burashnikov et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 25637381, 26707467, 20817017)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000437912	SCV000538571	uncertain significance	not specified	2017-03-01	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: HGMD 1 proband with early repolarization syndrome. LB in Amendola 2015. ClinVar 1 star review Ambry VUS, ESP LB
Invitae	RCV000693237	SCV000821097	uncertain significance	Brugada syndrome 4	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 73 of the CACNB2 protein (p.Ala73Val). This variant is present in population databases (rs200367454, gnomAD 0.02%). This missense change has been observed in individual(s) with idiopathic ventricular fibrillation (PMID: 20817017). ClinVar contains an entry for this variant (Variation ID: 161209). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNB2 protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000693237	SCV000896043	uncertain significance	Brugada syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000693237	SCV001138008	benign	Brugada syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000999569	SCV001156265	uncertain significance	Sudden unexplained death	2018-02-27	criteria provided, single submitter	research	CACNB2 Ala72Val has been previously reported in a case of idiopathic VF (Burashnikov E, et al., 2010) but has also been classified as likely benign in a study on the NHLBI exome sequencing project (Amendola LM, et al., 2015). We identified this variant in a sudden unexplained death case. The variant is present in the Genome Aggregation Database (MAF= 0.00009, http://gnomad.broadinstitute.org/), at an allele frequency which is higher then expected for an arrhythmia syndrome. In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, the variant is seen at an elevated frequency in the general population but in silico tools predict it to be deleterious, therefore we classify CACNB2 Ala72Val as a variant of 'uncertain significance'.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000693237	SCV002767560	uncertain significance	Brugada syndrome 4	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0111 - The inheritance pattern for this gene is unknown. Inheritance information not provided by OMIM and ClinGen dispute the association of CACNB2 with Brugada syndrome. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (31 heterozygotes, 0 homozygotes). (I) 0309 - Alternative amino acid changes at the same position has been observed in gnomAD (v2 & v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated SH3 domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in a patient with idiopathic ventricular fibrillation (PMID: 20817017), and has also been classified as likely benign (PMID: 25637381). This variant has one benign, one likely benign, and six VUS entries in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) NB: This variant has been reclassified as a VUS with low clinical relevance. It was previously reported as NM_000724.3(CACNB2):c.215C>T; p.(Ala72Val).
CSER _CC_NCGL, University of Washington	RCV000148447	SCV000190146	likely benign	Paroxysmal familial ventricular fibrillation	2014-06-01	no assertion criteria provided	research