Do all gene variants affect health and development?

No; only a small percentage of variants cause genetic disorders—most have no impact on health or development. For example, some variants alter a gene's DNA sequence but do not change the function of the protein made from the gene.

Often, gene variants that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed and an altered protein is produced. Each cell has a number of pathways through which enzymes recognize and repair errors in DNA. Because DNA can be changed or damaged in many ways, DNA repair is an important process by which the body protects itself from disease.

A very small percentage of all variants actually have a positive effect. These variants lead to new versions of proteins that help an individual better adapt to changes in his or her environment. For example, a beneficial variant could result in a protein that protects an individual and future generations from a new strain of bacteria.

Because a person's genetic code can have many variants with no effect on health, diagnosing genetic disorders can be difficult.

When determining if a gene variant is associated with a genetic disorder, the variant is evaluated using scientific research to date, such as information on how the variant affects the function or production of the protein that is made from the gene and previous variant classification data. The variant is then classified on a spectrum based on how likely the variant is to lead to the disorder.

Gene variants, as they relate to genetic disorders, are classified into one of five groups:

• Pathogenic: The variant is responsible for causing disease. There is ample scientific research to support an association between the disease and the gene variant. These variants are often referred to as mutations.
• Likely pathogenic: The variant is probably responsible for causing disease, but there is not enough scientific research to be certain.
• Variant of uncertain significance (VUS or VOUS): The variant cannot be confirmed to play a role in the development of disease. There may not be enough scientific research to confirm or refute a disease association or the research may be conflicting.
• Likely benign: The variant is probably not responsible for causing disease, but there is not enough scientific research to be certain.
• Benign: The variant is not responsible for causing disease. There is ample scientific research to disprove an association between the disease and the gene variant.

Evaluation needs to be done for each variant. Just because a gene is associated with a disease, does not mean that all variants in that gene are pathogenic. Additionally, evaluation of a variant needs to be done for all diseases with which it is thought to be associated. A variant that is pathogenic for one disease, is not necessarily pathogenic for a different disease. It is important to re-evaluate variants periodically; the classification of a variant can change over time as more information about the effects of variants becomes known through additional scientific research.

Scientific journal article for further reading

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. PMID: 25741868; PMCID: PMC4544753.