Changes and variation in CACNA1C

Timothy Syndrome and other CACNA1C-Related Disorders (CRDs) are caused by rare variants in the CACNA1C gene.

This page will explain:

• what a gene is
• why changes in the gene are called variants
• what makes a change common or rare

It will also cover when and how these changes cause problems, and lead to Timothy Syndrome and CRDs.

Your genetics and how it makes proteins

The genetic code which makes us up is different in every person, and this is what makes us individual and unique. Your genetic code is made of a long string of proteins. These are called deoxyribonucleic acid (DNA), bases, or nucleotides. There are four types of bases (A, G, C, T), which you can consider letters in the chain or string. The string that makes a human genome is 3.2 billion bases long. Sections of this string, when read together as a group, code for your cells to generate specific proteins, in the same way a group of letters read together can form a word, and those words form a sentence. When a section of genetic code can be read together to form a protein, it is called a gene. A long group of bases form the CACNA1C gene, which forms a specific protein for a calcium channel, Cav1.2.

Changes in the DNA code string that make up genes such as CACNA1C have multiple different names. Scientists, clinicians and researchers divide types of genetic variants into several categories, which can include; common variants or single nucleotide polymorphisms, rare variants or single nucleotide variants, and copy number variants. There are other categories, but these have not been linked to CRDs.

Common changes

There are many sections of the human genome which can have different changes between people. These changes are where one of the bases has swapped, for example, from an A to a G. Bases are ‘read’ in groups of three, called a ‘codon’. These mean that when the cell ‘reads’ the string of bases, there is a change in the protein, which can alter the way the protein works, like the way changing from the spelling ‘hit’ to ‘hat’ changes the word’s meaning. These changes are a large part of what makes us unique individuals.

Many of these changes alter the proteins in ways that cause positives and negatives. When they occur in more than 1% of the population, meaning more than 1 person in 100 carries that change, it is called a common variant. In clinical and research settings, these changes are also called single nucleotide polymorphisms; single – a single site, nucleotide – a specific base, polymorphism – a more common change. This is abbreviated to SNPs (pronounced ‘snips’).

Common variants, or SNPs, in the CACNA1C gene have been strongly linked to a range of common mental health and neurodevelopmental conditions. This means that some people in the population can have a specific base/ nucleotide at those sites (or a locus) in CACNA1C that predisposes them to develop a range of mental health and neurodevelopmental conditions. These studies have been done on tens of thousands of people, but the actual effect in each individual person is so tiny that most doctors won’t consider it adding a risk to that person developing a specific condition.

Sometimes common variants in CACNA1C are tested as part of panels for medication, therapeutic or lifestyle reasons. These can also be found through whole exome and whole genome sequencing. These might be reported as part of the test, indicating the link to common mental health and neurodevelopmental conditions. These common variants do not cause CRDs, and individuals should discuss any test results with their clinical team.

Rare changes

Rarer changes, or variants, also contribute a lot to our uniqueness and individuality. These changes occur in less than 1% of the population, so fewer than 1 in 100 people will carry that specific change. Often that change is unique to that person. When that change is in that person and not inherited from their parents, we call it de novo, meaning newly arisen. Rare variants can also be called single nucleotide variants in clinical and scientific settings; single – a single site, nucleotide – a specific base, variant – a change.

Rare variants alter the way proteins work in ways that have bigger effects. These can be positive or negative, and sometimes stop the protein from being made at all. TS and CRDs are caused by rare variants. TS is caused by changes which cause the Cav1.2 channel to work differently, and stop managing calcium flow in the cell as well. For many of the changes which cause CRDs, we don’t know what the change is doing to the channel, and this is a hot topic for research.

Another type of rare change are copy number variants, or CNVs. These are where larger sections of genetic code get copied, moved or deleted altogether. This can be imagined like taking the words from “the quick brown fox jumps over the lazy dog” and re-arranging it as “the quick jumps over the lazy brown fox dog”. Sometimes these re-arrangements make channels that work and sometimes they do not. Some CNVs have been linked to CRDs, but these are very rare, making it difficult to be sure about the effects they can cause.

Your change

If you have had genetic testing, your report should include information about the genetic variant you have in CACNA1C. These are often written as either “c.1216G>A”, where the c._ will be a series of numbers corresponding to how far along the CACNA1C gene the change is, while the > will be the change in the base that is at that spot on the gene. This can also be written as something like “G406R”, which is shorthand where the numbers correspond to how far along the protein that is made the change is, and the letters are the change in the parts of the protein. If you sign up to the TSA CACNA1C Community Registry, we will ask for this information.