The 29th of February is not just a leap-year day; it is also Rare Disease Day (http://www.rarediseaseday.org/). It is estimated that 80% of rare diseases are of genetic origin. Organizations such as the Genetic Alliance (http://www.geneticalliance.org/) emphasize that hereditary genetic diseases are collectively rather common and, being familial disorders, affect the quality of life of relatives as well as affected individuals. If we are to make an impact on this considerable burden of disease, we need end-to-end control of the entire process from variant discovery and evaluation to the creation of guidelines for use in medicine, which is currently fragmented across multiple specialized organizations. These stakeholders do what they do well and need encouragement to connect their efforts.

Variant discovery can happen in the clinic. Several organizations exist that are dedicated to harmonizing and evaluating the gene-based tests that make this discovery possible, including EuroGentest (http://www.eurogentest.org/) and GeneTests (http://www.ncbi.nlm.nih.gov/sites/GeneTests/). Most variants that are discovered in the research laboratory are now identified through high-throughput efforts, such as exome sequencing (for example, http://evs.gs.washington.edu/EVS/).

The effort of databasing and curation entails standard genetic and phenotypic nomenclature as well as appropriate software development and data standards projects (http://www.gen2phen.org/resources). Phenotypic description needs to be standardized to medical ontologies, such as the Systemized Nomenclature of Medicine–Clinical Terms (SNOMED CT; http://www.ihtsdo.org/snomed-ct/) and the International Classification of Disease 11th Revision (ICD-11; http://www.who.int/classifications/icd/revision/en/index.html), which have themselves been updated to accommodate genetic terms and to distinguish constitutional from acquired conditions.

Variants in a gene, disease or pathway can be collected, databased and published via a microattribution review (Nat. Genet. 43, 295–301, 2011). Ideally, this type of community annotation exercise should also include assessment of the evidence that the particular variants found are likely to be the cause of disease by both experts and clinical users of genetic diagnostics. One model showing how this may be done is presented in a paper by Spurdle et al. (Hum. Mutat. 33, 2–7, 2012 ). In this article on breast cancer risk, the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA; http://enigmaconsortium.org/) present their framework for 'evidence of pathogenicity', including variants of unknown significance.

Assessment of genotypes at a single locus and in oligogenic combinations has been attempted in the field of pharmacogenetics. Here again, the model is collaborative evaluation involving the combined efforts of practitioners in the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (Clin. Pharmacol. Ther. 89, 464–467, 2011; http://www.pharmgkb.org/contributors/consortia/cpicgene-drug_pairs.jsp). The final product of this exercise is then suitable for instantiation in an electronic record system to provide decision support in the pharmacy and to the physician prescribing drugs to a genotyped patient. Finally, the genetic variant information can be used to inform the disease-specific information pages generated by Orphanet (http://www.orpha.net/consor/cgi-bin/index.php) and the National Institutes of Health (NIH) Office of Rare Diseases Research (http://rarediseases.info.nih.gov/), which in turn inform patients, physicians and researchers.

Two international organizations provide overall coordination of all of these steps and create venues for discussion, encouraging stakeholders to see the bigger context in which they work. The first is the Human Genome Organisation (HUGO), which holds its Human Genome Meeting this month (11–14 March in Sydney, Australia; http://www.hugo-international.org/hugoevents.php?event=humangenome). The other coordinator is the Human Variome Project (HVP), which this month is seeking input on its roadmap for the next four years (http://www.humanvariomeproject.org/). Discussion of the grand pipeline will be the subject of the HVP Biennial Meeting to be held 11–15 June 2012 at UNESCO in Paris, France.