ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

CACNA1C encodes a subunit (L-type, alpha-1C) of a voltage-dependent calcium channel that functions in cardiac muscle to regulate conduction. Although numerous sequence-level mutations in CACNA1C have been reported in association with cardiac conduction abnormalities (e.g. Brugada syndrome 3, Timothy syndrome, Long QT syndrome), none are predicted to result in a complete loss-of-function (null mutations). Functional studies of the CACNA1C mutations associated with Brugada syndrome and related phenotypes have provided some evidence to support a loss-of-function type mechanism of pathogenicity (Antzelevitch et al 2007; Burashnikov et al. 2010). However, expression studies have indicated that these are not in fact null mutations, and there is some controversy regarding the phenotypic association in these studies (Wilde and Ackerman 2010). Thus far, a focal CACNA1C deletion has not been reported. Several patients with large, non-focal CACNA1C deletions have been reported in the literature (Rooryck et al. 2009; Macdonald et al. 2010; Abdelmoity et al. 2011; Thevenon et al. 2013; Fanizza et al. 2014). The majority of these studies involve pediatric /adolescent patients carrying de novo mutations; however, two studies have characterized deletions that were found in both a parent and their child. In cases where cardiac conduction has been assessed, cardiac arrhythmia related phenotypes have not been consistently observed. However, cardiac conduction phenotypes are often adult age in onset, and an incomplete penetrance for these phenotypes may complicate this analysis. Wemhoner et al (2015, PMID 25633834) identified two patients with variants at p.Ile1166. One individual had p.Ile1166Thr and a phenotype consistent with TS while the other patient had p.Ile1166Val and a LQTS-only phenotype. Each variant also led to distinct electrophysiological characteristics. In another example, they found a patient with a three base-pair deletion (p.Glu850del) as described previously by Burashnikov et al (2010). Wemhoner et al?s patient had LQTS, and not early repolarization syndrome as described by Burashnikov. These examples suggest that mutation location may not be the final determinant of disease manifestation. Boczek et al (2015, PMID 26253506) summarized that the ?disease phenotypes observed with mutations in the calcium channel are more complex than the location of the mutation within the channel and the underlying electrophysiological perturbations that the particular mutation causes.? They suggested the that amino acid change itself, the binding partner proteins leading to complex signaling cascades, or other genetic or epigenetic factors may play a role in the disease pathogenesis causing different CACNA1C mutations to lead to the varied phenotypes observed. Given the current limited evidence for CACNA1C haploinsufficiency, the haploinsufficiency score for this gene is a 1.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity