CACNA1C

Inheritance Pattern: AD

Disease ID:MONDO:0010979

Submitter: ClinGen

CACNA1C was first reported in relation to Timothy syndrome (TS) in 2004 (Splawski et al., PMID: 15454078). TS is a novel disorder characterized by multiorgan dysfunction including arrhythmias, syndactyly, cardiac features, immune deficiency and neurological and developmental abnormalities. Two recurrent de novo variants on exon 8 and 8a (G406R and G402S) that have been reported in over 14 probands in 11 publications (PMIDs: 15454078, 15863612, 22106044, 23678275, 27390944, 16360093, 24773605, 23580742, 29194862, 27593853, 28371864) are included in this curation. Of note variants p.Arg518Cys/His seemingly have an isolated cardiac phenotype seen in 9 probands. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be gain of function caused by missense variants. This gene-disease relationship is also strongly supported by animal models and expression studies (PMIDs: 8392192, 23045342, 21878566, 21216955). In summary, CACNA1C is definitively associated with Timothy syndrome. This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This classification was approved by the Hereditary Cardiovascular Disease Gene Curation Expert Panel on April 14, 2023.

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: ClinGen

CACNA1C encodes for the alpha-1c subunit of the voltage-dependent L-type calcium channel which is important for the development of the action potential in human cardiomyocytes. Genetic variants in this gene have been identified in 5 probands with suggested SQTS phenotype. Three of these probands, however, had Brugada syndrome with a relatively short QT interval (PMIDs 17224476, 20817017) and one had hypertrophic cardiomyopathy without a convincing SQTS phenotype (PMID 28427417). Accordingly, the SQTS Gene Curation Expert Panel decided these patients did not have an isolated SQTS phenotype and the genetic evidence derived from these cases should not be scored toward relationship of CACNA1C with SQTS. The final proband was identified as having a de novo variant (PMID 24291113), however, the gnomAD MAF was regarded as too high for a rare condition such as SQTS and there was no other evidence supporting this variant’s impact.

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: ClinGen

CACNA1C encodes the alpha-1 subunit (Cav1.2) of the L-type voltage-dependent calcium channel, and colocalizes with RYR in the sarcolemma membrane, indicating a functional role in calcium handling [PMID: 23045342]. CACNA1C expression is observed in cardiac, cerebral, pulmonary, and smooth muscle tissues [PMID: 8392192 & 15454078]. Variants in CACNA1C can disrupt the function of the calcium ion channel and potentially cause arrhythmias. The following summarizes the updated gene curation. CACNA1C and its association with Brugada syndrome was reported in 2007 by Anzelevitch et al., with two Brugada syndrome patients identified with missense variants (G490R & A39V) in CACNA1C [PMID: 17224476]. However, reviewing recent population databases (GnomAD) revealed the G490R variant was too frequent in healthy populations to be a causative factor for Brugada Syndrome. Burashnikov et al. (2010) identified 9 CACNA1C variants in probands with Brugada Syndrome, Brugada syndrome exhibiting shorter than normal QT intervals, and early repolarization syndrome. Four variants were of interest and absent or rare in gnomAD (p.E1115K, p.A39V, p.E1829_Q1833dup, p.C1837Y), while the remaining five variants were considered common in gnomAD [PMID: 20817017]. Another study in 2013 by Risgaard et al., reported four CACNA1C variants (p.G490R, p.C1837Y, p.R1880Q, V2014I) in 19 probands from the NHLBI GO Exome Sequencing Project. Out of the four, only one was absent or rare in gnomAD (p.C1837Y). The authors noted the cohort lacked provocation testing, some may have been asymptomatic carriers and the mean age was >60 years, which is older than the typical age of diagnosis for Brugada syndrome. Novelli et al. (2022) reported 12 SCN5A-negative Brugada probands with variants in CACNA1C. However five were absent or rare in gnomAD and scored (p.Q428E, p.E850D, p.N1255S, p.G2084E, c.5589-1G>A) [PMID: 34999275] CACNA1C and its association with Brugada syndrome was evaluated by the Hereditary Cardiovascular GCEP on November 21, 2017. We reviewed this again on February 25, 2025 (SOP v 11). Although new case and cohort studies have been published since 2017 [PMID: 34999275], conflicting evidence remains. Many reported variants in CACNA1C are too common in population databases, and functional studies have shown that both common and rare variants can produce similar effects [PMID: 17224476, 20817017]. The GCEP therefore agreed to maintain the gene–disease classification of CACNA1C and Brugada syndrome as disputed.

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0010979

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0032756

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0010979

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012742

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0010979

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0859286

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012742

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012742

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: ClinGen

CACNA1C encodes for the alpha-1c subunit of the voltage-dependent L-type calcium channel which is important for the development of the action potential in human cardiomyocytes. Pathogenic variants in CACNA1C are the cause for Timothy Syndrome, a rare multi-organ disorder whose manifestations include QT prolongation and ventricular arrhythmias (PMID 15454078). Boczek at al. were the first to identify a variant in CACNA1C in a family with genotype-negative cardiac-specific typical LQTS (PMID 23677916). They performed exome sequencing of 3 members of the family and filtered the shared genetic variants identified using bioinformatics tools. Several other studies have provided additional genetic and experimental evidence to support the association of CACNA1C with typical LQTS, however, no segregation or case-control data is available and the overall level of evidence for this association was classified by the Working Group as moderate. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the LQTS Clinical Domain Working Group. The classification and summary presented here is the conclusion of this Working Group's analysis according to evidence available at time of publication. The scores presented here are the result of only one of the three curation teams' efforts. For a detailed discussion of this group's work and the scores of all 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”