ClinVar Miner

Submissions for variant NM_201596.3(CACNB2):c.1580A>C (p.Lys527Thr)

gnomAD frequency: 0.00003  dbSNP: rs771565696
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483244 SCV000569175 uncertain significance not provided 2016-01-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNB2 gene. The K472T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K472T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K472T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where only amino acids with similar properties to Lysine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CACNB2-related disorders (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Invitae RCV001856841 SCV002209545 uncertain significance Brugada syndrome 4 2023-07-28 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 420365). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 473 of the CACNB2 protein (p.Lys473Thr). This variant is present in population databases (rs771565696, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. 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. 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 RCV002395156 SCV002697295 uncertain significance Cardiovascular phenotype 2023-08-29 criteria provided, single submitter clinical testing The p.K473T variant (also known as c.1418A>C), located in coding exon 13 of the CACNB2 gene, results from an A to C substitution at nucleotide position 1418. The lysine at codon 473 is replaced by threonine, an amino acid with similar properties. This amino acid position is well 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.

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