The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources

PURPOSE Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease, and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed. METHODS The GenCC drafted harmonized definitions for differing levels of gene-disease validity based on existing resources, and performed a modified Delphi survey with three rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members. RESULTS Based on 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contains 15,241 gene-disease assertions on 4,569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%. CONCLUSION Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation. ### Competing Interest Statement Conflict of Interest: R.E.F. is an employee of SciBite Ltd, an Elsevier company. Her work towards this paper was performed when employed by Genomics England. The following authors are an employee for a commercial laboratory that offers clinical genetic testing: M.B.; A.J.C.; K.R.; J.T.. All other authors have nothing to disclose. ### Funding Statement This study was supported by the National Human Genome Research Institute of the National Institutes of Health under award U24HG006834. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other affiliations. This work was supported by the Intramural Research Program at the National Library of Medicine. PanelApp Australia is supported by Australian Genomics (NHMRC Grants GNT1113531 and GNT2000001). This work was supported by Wellcome Trust [107469/Z/15/Z; 200990/A/16/Z], Medical Research Council (UK), British Heart Foundation [RE/18/4/34215], the NIHR Imperial College Biomedical Research Centre. We thank all PanelApp reviewers and those who have contributed feedback or gene lists to help in the development of PanelApp;individual panels show the names and affiliations of contributors. We thank all participants in the 100,000 Genomes Project. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health). The 100,000 Genomes Project is funded by the NIHR and NHSE. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the NHSE as part of their care and support. Open Targets is supported by Open Targets. The work performed by authors at EMBLEBI was supported by the Wellcome Trust [WT200990/Z/16/Z]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data from the GenCC website is openly available in multiple download formats and can be accessed here (). A snapshot of the GenCC database (Dec 2021) relevant to the figures and analysis in this manuscript can be found in the supplemental files. Deidentified Delphi survey responses are available upon request (email mdistefa{at}broadinstitute.org).