Utilizing ClinGen gene‐disease validity and dosage sensitivity curations to inform variant classification

Abstract

Understanding whether there is enough evidence to implicate a gene's role in a given disease, as well as the mechanisms by which variants in this gene might cause this disease, is essential to determine clinical relevance. The National Institutes of Health-funded Clinical Genome Resource (ClinGen) has developed evaluation frameworks to assess both the strength of evidence supporting a relationship between a gene and disease (gene-disease validity), and whether loss (haploinsufficiency) or gain (triplosensitivity) of individual genes or genomic regions is a mechanism for disease (dosage sensitivity). ClinGen actively applies these frameworks across multiple disease domains, and makes this information publicly available via its website (https://www.clinicalgenome.org/) for use in multiple applications, including clinical variant classification. Here, we describe how the results of these curation processes can be utilized to inform the appropriate application of pathogenicity criteria for both sequence and copy number variants, as well as to guide test development and inform genomic filtering pipelines.