PT - JOURNAL ARTICLE AU - Natasha T. Strande AU - Erin Rooney Riggs AU - Adam H. Buchanan AU - Ozge Ceyhan-Birsoy AU - Marina DiStefano AU - Selina S. Dwight AU - Jenny Goldstein AU - Rajarshi Ghosh AU - Bryce A. Seifert AU - Tam P. Sneddon AU - Matt W. Wright AU - Laura V. Milko AU - J. Michael Cherry AU - Monica A. Giovanni AU - Michael F. Murray AU - Julianne M. O’Daniel AU - Erin M. Ramos AU - Avni B. Santani AU - Alan F. Scott AU - Sharon E. Plon AU - Heidi L. Rehm AU - Christa L. Martin AU - Jonathan S. Berg TI - Evaluating the clinical validity of gene-disease associations: an evidence-based framework developed by the Clinical Genome Resource AID - 10.1101/111039 DP - 2017 Jan 01 TA - bioRxiv PG - 111039 4099 - http://biorxiv.org/content/early/2017/04/13/111039.short 4100 - http://biorxiv.org/content/early/2017/04/13/111039.full AB - With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship, and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semi-quantitative measurement for the strength of evidence of a gene-disease relationship which correlates to a qualitative classification: “Definitive”, “Strong”, “Moderate”, “Limited”, “No Reported Evidence” or “Conflicting Evidence.” Within the ClinGen structure, classifications derived using this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.