Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000646207 | SCV000767966 | uncertain significance | Brugada syndrome 4 | 2022-08-16 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 269 of the CACNB2 protein (p.Ala269Thr). This variant is present in population databases (rs561197163, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 537373). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. |
| Centre for Mendelian Genomics, |
RCV000646207 | SCV001367446 | uncertain significance | Brugada syndrome 4 | 2019-11-18 | criteria provided, single submitter | clinical testing | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001260307 | SCV001437230 | benign | not specified | 2020-09-08 | criteria provided, single submitter | clinical testing | Variant summary: CACNB2 c.805G>A (p.Ala269Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251284 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 33-fold the estimated maximal expected allele frequency for a pathogenic variant in CACNB2 causing Brugada Syndrome phenotype (3.1e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.805G>A in individuals affected with Brugada Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. |
| Ambry Genetics | RCV002422348 | SCV002678444 | uncertain significance | Cardiovascular phenotype | 2021-11-08 | criteria provided, single submitter | clinical testing | The p.A269T variant (also known as c.805G>A), located in coding exon 9 of the CACNB2 gene, results from a G to A substitution at nucleotide position 805. The alanine at codon 269 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. |