Clinical and research laboratories extensively use exome sequencing due to its high diagnostic rates, cost savings, impact on clinical management, and efficacy for disease gene discovery. While the rates of disease gene discovery have steadily increased, only ~16% of genes in the genome have confirmed disease associations. Here we describe our diagnostic laboratory’s disease gene discovery and ongoing data-sharing efforts with GeneMatcher. In total, we submitted 246 candidates from 243 unique genes to GeneMatcher, of which 45.93% are now clinically characterized. Submissions with at least one case meeting our candidate genes reporting criteria were significantly more likely to be characterized as of October 2021 compared to genes with no candidates meeting our reporting criteria (p=0.025). We reported relevant findings related to these gene-disease associations for 480 probands. In 219 (45.63%) instances, these results were reclassifications after an initial candidate gene (uncertain) or negative report. Since 2013, we have co-authored 105 publications focused on delineating gene-disease associations. Diagnostic laboratories are pivotal for disease gene discovery efforts and can screen phenotypes based on genotype matches, contact clinicians of relevant cases, and issue proactive reclassification reports. GeneMatcher is a critical resource in these efforts.