Mutations in the CACNA1C gene are responsible for all reported cases of Timothy syndrome. One mutation has been found in everyone diagnosed with classic, or type 1, Timothy syndrome. This mutation changes one protein building block (amino acid) used to build the channel. Specifically, the mutation replaces the amino acid glycine with the amino acid arginine at position 406 (written as Gly406Arg or G406R).

The mutation that causes classic Timothy syndrome occurs in exon 8A, and is present only in the version of the CaV1.2 channel made with this segment. Therefore, in the brain and heart, the mutation affects about 20 percent of all CaV1.2 channels.

Two mutations in the CACNA1C gene cause a more severe, atypical form of Timothy syndrome called type 2. These mutations occur in the version of the CaV1.2 channel made with exon 8. One of these genetic changes, G406R, is the same mutation that causes classic Timothy syndrome when it occurs in exon 8A. The other mutation replaces the amino acid glycine with the amino acid serine at position 402 (written as Gly402Ser or G402S).

Because the mutations responsible for atypical Timothy syndrome occur in exon 8, they are present only in versions of the CaV1.2 gene that contain this segment. In the brain and heart, this version accounts for about 80 percent of all CaV1.2 channels. Researchers believe that the more severe features of atypical Timothy syndrome result from the higher percentage of mutated channels in heart and brain cells.

Mutations in the CACNA1C gene change the structure of CaV1.2 channels throughout the body. The altered channels stay open much longer than usual, which allows calcium ions to continue flowing into cells abnormally. The resulting overload of calcium ions within cardiac muscle cells changes the way the heart beats and can cause arrhythmia. Researchers are working to determine how an increase in calcium ion transport in other tissues, including cells in the brain, underlies the other features of Timothy syndrome.

Excerpt from:
CACNA1C gene - Genetics Home Reference - NIH