ClinVar Miner

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

gnomAD frequency: 0.00022  dbSNP: rs200367454
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Total submissions: 9
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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,, 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

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