Basics


Discussions regarding the uniform and unequivocal description of sequence variants in DNA and protein sequences (mutations, polymorphisms) were initiated by two papers published in 1993 (Beaudet AL & Tsui LC and Beutler E). The ideas presented were widely discussed, modified, extended (see History) and ultimately resulted in the HGVS nomenclature, the recommendations for the description of sequence variants, based on a paper published in 2000 (den Dunnen, JT and Antonarakis, SE). Initially these recommendations did not extensively cover all types of variants and more complex changes. This website was established to give an up-to-date overview of all recommendations, the changes made and the extensions approved. In addition the web site provides background information, examples of descriptions based on the nomenclature and link to support tools and educational material. These pages can be used as a guide to describe any sequence variant identified and should help to get a uniformly accepted standard.

The HGVS nomenclature is authorised by the Human Genome Variation Society (HGVS), the Human Variome Project (HVP) and the HUman Genome Organisation (HUGO). Activities regarding the nomenclature go through a committee, the Sequence Variant Description Working Group (SVD-WG), with administrative support of the HVP office (see HVP website).

The SVD-WG takes care of this website, answers questions, handles requests to change or extend the recommendations, prepares proposals for community consultation, publishes new versions of the standards and assigns HGVS nomenclature version numbers. Any proposal made by the SVD-WG will be published on this website and opened for a 2-month period of Community Consultation. During this period everybody interested is asked to study the proposal and send comments, positive or negative, to the committee. Comments to proposals should be addressed to “Varnomen @ variome.org”, Subject: SVD-WGxxx (xxx the proposal number, e.g. SVD-WG001). After two months the committee will collect all responses, evaluate them and take a decision. Proposals might be approved, rejected or modified for a new round of consultation. All decisions will be published on this website. To make sure that you receive notification of any proposal published for Community Consultation, please register at the HVP office (E-mail to Timothy Smith (Tim @ Variome.org), Subject: SVD-WG discussion list). For proposals open for Community Consultation and issues currently discussed, see Open Issues.


Versioning

The recommendations for the description of sequence variants are designed to be stable, meaningful, memorable and unequivocal. Still, every now and then small modifications will be required to remove inconsistencies and/or to clarify confusing conventions. In addition, the recommendations may be extended to resolve cases that were hitherto not covered. To allow users to specify up to what point they follow HGVS nomenclature, version numbers will be assigned.

Since 2015, any change in the recommendations receives a new version number. The version number will be based on the date of the change. Both in the version list, and on the page containing the change, the version number assigned will be clearly marked. The version number will have the format: HGVS nomenclature Version 15.11, for the version accepted in 2015 (“15”), November (“11”).

The current HGVS version number is shown in the top right corner of this web site (“Version xx.xx”). Note that the version number remains as is when only a typing error is corrected, an example added, an explanation clarified, a question answered, etc.


Terminology

Considerable effort has been invested to use only clearly defined terms. For details see our Glossary.

Mutation and polymorphism

In some disciplines the term “mutation” is used to indicate “a change” while in other disciplines it is used to indicate “a disease-causing change”. Similarly, the term “polymorphism” is used both to indicate “a non disease-causing change” or “a change found at a frequency of 1% or higher in a population”. To prevent this confusion we do not use the terms mutation and polymorphism (including SNP or Single Nucleotide Polymorphism) but neutral terms like “sequence variant”, “alteration” and “allelic variant”. Vol.19(1) of Human Mutation (2002) contains several contributions discussing the issues and shows that the term “mutation” has developed a negative connotation (see Cotton RGH - p.2, Condit CM et al. - p.69 and Marshall JH - p.76). Who would like to carry a mutation and thus be a “mutant”?? Current guidelines of authorative organisations now also recommend to use neutral terms like “variant” and “change” only (see Richards 2015, Genet.Med. 17:405-424).

Pathogenic

Another confusing term used frequently is “a pathogenic variant”. A variant in itself is not “pathogenic”, whether it can be causally related to a phenotype observed in a patient is determined by other factors. While a non-expert concludes the variant described “causes disease”, the expert probably means “causes disease when in a specific context”, e.g:

Another problem emerges when variants need to be classified that determine non-disease phenotypes like lactose tolerance/persistence, bitter tasting or hair and skin colour. What is pathogenic in the MC1R gene: dark, blond, or red hair? What ends up in the SLC24A5 database as the pathogenic skin color: light or dark skin?

To prevent confusion it therefore seems better not to use the term “pathogenic”. For variant classification a good alternative is a specific but neutral term like “affects function”. This properly describes what one actually means, the variant affects the normal function of the gene/protein (in whatever way). It also solves the issue of what term to use for non-disease phenotypes like skin/hair/eye colour. To indicate that in an individual variant(s) were found that can explain the disease phenotype an alternative for “pathogenic” is to use “disease-associated variant”. For variant classification people use most frequently five categories. Based on affects function these could be; affects function, probably affects function, unknown (or effect on function not known), probably does not affect function (or probably no functional effect), does not affect function (or no functional effect).