Submissions for variant NM_201596.3(CACNB2):c.1123G>A (p.Ala375Thr)

gnomAD frequency: 0.00002  dbSNP: rs552868927

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170880	SCV000223435	uncertain significance	not provided	2014-11-12	criteria provided, single submitter	clinical testing	p.Ala320Thr (GCG>ACG): c.958 G>A in exon 10 of the CACNB2 gene (NM_000724.3). A variant of unknown significance has been identified in the CACNB2 gene. The A320T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A320T 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 A320T 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported indicating this region of the protein may tolerate 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 BRUGADA panel(s).
Ambry Genetics	RCV002381544	SCV002694152	uncertain significance	Cardiovascular phenotype	2022-07-28	criteria provided, single submitter	clinical testing	The p.A321T variant (also known as c.961G>A), located in coding exon 10 of the CACNB2 gene, results from a G to A substitution at nucleotide position 961. The alanine at codon 321 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.
Invitae	RCV002517642	SCV003469379	uncertain significance	Brugada syndrome 4	2022-11-18	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs552868927, gnomAD 0.004%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 190735). This missense change has been observed in individual(s) with clinical features of arrhythmogenic cardiomyopathy and/or unknown arrhythmia (PMID: 30847666). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 321 of the CACNB2 protein (p.Ala321Thr).
Clinical Genetics, Academic Medical Center	RCV000170880	SCV001918692	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000170880	SCV001955547	uncertain significance	not provided		no assertion criteria provided	clinical testing