ClinVar Miner

Submissions for variant NM_201596.3(CACNB2):c.1681G>A (p.Glu561Lys)

gnomAD frequency: 0.00006  dbSNP: rs199714857
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000697967 SCV000826603 uncertain significance Brugada syndrome 4 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 507 of the CACNB2 protein (p.Glu507Lys). This variant is present in population databases (rs199714857, gnomAD 0.03%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 575677). 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.
Ambry Genetics RCV002388284 SCV002708146 uncertain significance Cardiovascular phenotype 2022-01-12 criteria provided, single submitter clinical testing The p.E507K variant (also known as c.1519G>A), located in coding exon 13 of the CACNB2 gene, results from a G to A substitution at nucleotide position 1519. The glutamic acid at codon 507 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a Brugada syndrome cohort (Di Resta C et al. Hum Mol Genet, 2015 Oct;24:5828-35). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000697967 SCV002767514 uncertain significance Brugada syndrome 4 2020-07-02 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. An inheritance pattern has not been provided by OMIM and ClinGen dispute its association with Brugada syndrome. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (23 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has one VUS entry in ClinVar and has previously been classified as a VUS with low clinical relevance in a Brugada patient tested at VCGS. (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) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV000697967 SCV002793423 uncertain significance Brugada syndrome 4 2021-10-13 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV004792400 SCV005410966 uncertain significance not provided 2024-08-20 criteria provided, single submitter clinical testing

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