Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000617371 | SCV000738159 | uncertain significance | Cardiovascular phenotype | 2020-02-26 | criteria provided, single submitter | clinical testing | The p.V514L variant (also known as c.1540G>C), located in coding exon 13 of the CACNB2 gene, results from a G to C substitution at nucleotide position 1540. The valine at codon 514 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193384 | SCV001362166 | uncertain significance | not specified | 2019-05-13 | criteria provided, single submitter | clinical testing | Variant summary: CACNB2 c.1540G>C (p.Val514Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251242 control chromosomes (gnomAD). The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNB2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1540G>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
| Invitae | RCV002531799 | SCV003262479 | uncertain significance | Brugada syndrome 4 | 2022-02-06 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 514 of the CACNB2 protein (p.Val514Leu). This variant is present in population databases (rs142639223, gnomAD 0.03%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 519506). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. |