The DNA sequence of a gene can be altered in a number of ways. Gene variants (also known as mutations) can have varying effects ­­on health, depending on where they occur and whether they alter the function of essential proteins. Variant types include the following:

Substitution

This type of variant replaces one DNA building block (nucleotide) with another. Substitution variants can be further classified by the effect they have on the production of protein from the altered gene.

• Missense: A missense variant  is a type of substitution in which the nucleotide change results in the replacement of one protein building block (amino acid) with another in the protein made from the gene. The amino acid change may alter the function of the protein.

• Nonsense: A nonsense variant  is another type of substitution. Instead of causing a change in one amino acid, however, the altered DNA sequence results in a stop signal that prematurely signals the cell to stop building a protein. This type of variant results in a shortened protein that may function improperly, be nonfunctional, or get broken down.

Insertion

An insertion changes the DNA sequence by adding one or more nucleotides to the gene. As a result, the protein made from the gene may not function properly.

Deletion

A deletion changes the DNA sequence by removing at least one nucleotide in a gene. Small deletions remove one or a few nucleotides within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the affected protein or proteins.

Deletion-Insertion

This variant occurs when a deletion and insertion happen at the same time in the same location in the gene. In a deletion-insertion variant, at least one nucleotide is removed and at least one nucleotide is inserted. However, the change must be complex enough to differ from a simple substitution. The resulting protein may not function properly. A deletion-insertion (delins) variant may also be known as an insertion-deletion (indel) variant.

Duplication

A duplication occurs when a stretch of one or more nucleotides in a gene is copied and repeated next to the original DNA sequence. This type of variant may alter the function of the protein made from the gene.

Inversion

An inversion changes more than one nucleotide in a gene by replacing the original sequence with the same sequence in reverse order.

Frameshift

A reading frame consists of groups of three nucleotides that each code for one amino acid. A frameshift variant occurs when there is an addition or loss of nucleotides that shifts the grouping and changes the code for all downstream amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift variants.

Repeat expansion

Some regions of DNA contain short sequences of nucleotides that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of sequences of three nucleotides, and a tetranucleotide repeat is made up of sequences of four nucleotides. A repeat expansion is a variant that increases the number of times that the short DNA sequence is repeated. This type of variant can cause the resulting protein to function improperly.