Submissions for variant NM_201596.3(CACNB2):c.1841G>A (p.Arg614Gln)

gnomAD frequency: 0.00003  dbSNP: rs367619172

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170882	SCV000223437	uncertain significance	not provided	2014-11-18	criteria provided, single submitter	clinical testing	p.Arg559Gln (CGA>CAA): c.1676 G>A in exon 13 of the CACNB2 gene (NM_000724.3). A variant of unknown significance has been identified in the CACNB2 gene. The R559Q variant has not been published as a mutation or as a benign polymorphism to our knowledge. The R559Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is highly conserved across species. The R559Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with Brugada syndrome indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in ARRHYTHMIA panel(s).
Invitae	RCV000802497	SCV000942331	uncertain significance	Brugada syndrome 4	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 560 of the CACNB2 protein (p.Arg560Gln). This variant is present in population databases (rs367619172, gnomAD 0.006%). 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: 190737). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
Ambry Genetics	RCV002399607	SCV002714480	uncertain significance	Cardiovascular phenotype	2023-10-12	criteria provided, single submitter	clinical testing	The p.R560Q variant (also known as c.1679G>A), located in coding exon 13 of the CACNB2 gene, results from a G to A substitution at nucleotide position 1679. The arginine at codon 560 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415682	SCV000493721	uncertain significance	Short QT Syndrome 5	2016-01-27	no assertion criteria provided	clinical testing