Submission Details

CACNB2 was first reported in relation to autosomal dominant cardiogenetic disease in 2007 (Antzelevitch et al., PMID: 17224476). CACNB2 encodes the β subunit of the L-type voltage gated calcium channel. It regulates trafficking and gating properties of the channel (PMID: 17224476). CACNB2 has been reported in relation to Brugada syndrome with supporting functional evidence, segregation data, and low gnomAD frequencies (PMIDs: 17224476, 19358333; ClinVar: SCV003918905.2); however there has been a lack of new evidence to emerge since these cases were published. CACNB2 has only been reported in relation to hypertrophic cardiomyopathy where it was asserted as a possible disease modifier in one Chinese family with a known pathogenic MYBPC3 variant (Zhang et al., PMID: 28614222). Note that this variant is common in the East Asian population (MAF= 0.01) and may be benign. The relationship of CACNB2 with short QT syndrome is based on a single report which used a candidate-gene approach in patients with Brugada syndrome and a short QT interval (PMID: 17224476). Because the proband identified as carrying the rare genetic variant (ClinVar Variation ID# 9547) had a positive ajmaline test, his phenotype was regarded by the Short QT Syndrome GCEP to be concordant with Brugada syndrome and not SQTS.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability between the cardiogenetic disease assertions. Therefore, the following disease entities have been lumped into one disease entity: Brugada syndrome 4 (OMIM:611876), hypertrophic cardiomyopathy (PMID: 28614222), and short QT syndrome (PMID: 17224476). We did find differences in the molecular mechanism, inheritance pattern, and phenotypic variability for the reports of CACNB2 in relation to autism, therefore the split curation for autism will be curated separately.

Three missense variants that have been reported in three probands in two publications (PMIDs: 17224476, 19358333) and one ClinVar entry (SCV003918905.2) are included in this curation. Many other CACNB2 variants have been reported in relation to cardiogenetic disease, but were not scored in this curation due to their allele frequency being above the cutoff established by the HCVD GCEP (>0.00005) or the presence of another variant (PMIDs: 20817017, 22840528, 22090166, 23414114, 26230511, 32824506, 27711072, 35955449, 31737537, 27662471, 28614222). The mechanism of pathogenicity is reported to be loss of function (PMID: 17224476).

This gene-disease relationship is also supported by expression studies in heart tissue (PMIDs: 24309898, 21357697, 34307509) and model organisms indicate it may play a role in hypertrophic pathways (PMIDs: 34307509, 17556655, 21357697, 16946137).

In summary, the evidence supporting the relationship between CACNB2 and autosomal dominant cardiogenetic disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role CACNB2 plays in cardiogenetic disease. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on the meeting date June 24, 2025 (SOP Version 11).