ABSTRACT
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, currently no standard guidelines for such evaluation exist. Thus 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. Relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship is evaluated semi-quantitatively and assigned a preliminary classification: “Definitive”, “Strong”, “Moderate”, “Limited”, “No Reported Evidence” or “Conflicting Evidence.” Classifications are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. 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.