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.
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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