Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000482157 | SCV000569206 | uncertain significance | not provided | 2016-01-21 | criteria provided, single submitter | clinical testing | A novel variant of uncertain significance has been identified in the CACNB2 gene. The K576E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although this variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, it has been reported at a low frequency (1/1006 alleles, 0.1%) in individuals of European ancestry in the 1000 Genomes Project. The K576E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved in mammals. Another missense variant in a nearby residue (R571C) has been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. |
| Labcorp Genetics |
RCV001341327 | SCV001535195 | uncertain significance | Brugada syndrome 4 | 2023-05-01 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs200613235, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 577 of the CACNB2 protein (p.Lys577Glu). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 420386). |