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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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