In summary, using decision support tools and human expert curation, we have developed an integrated approach to facilitate the application of comprehensive genetic testing to the clinical care of persons with hearing loss. We believe that detailed disease-specific knowledge of the genomic landscape is requisite to establish a framework for variant interpretation and show that there are gene-specific mutational signatures, the knowledge of which will refine guidelines for variant interpretation for deafness and advance our understanding of disease biology. This resource is freely available to the public and configurable to allow its implementation for any Mendelian genetic disorder.