Implementation, Manual Curation, and Override
The DVD was implemented in our internal NGS pipeline, which we use to generate a clinical report for each subject evaluated with our targeted gene panel OtoSCOPE.8 A multidisciplinary expert panel, including clinicians, geneticists, scientists, bioinformaticians, and genetic counselors, reviews all genetic results in the context of available phenotypic data. When the expert panel does not agree with the variant classification in the DVD, the variant is added to an internal list of manually curated variants with the revised classification. This list is continually updated and integrated back into the DVD to prevent the propagation of an incorrect variant classification. The manually curated list includes pathogenic variants that have been identified exclusively in our screen of more than 5,000 individuals with hearing loss, as these variants were not found in other public databases.8, 23, 24 It also includes known pathogenic variants with MAFs ≥ 0.5% (founder mutations and variants in specific genes, see Table S2), which have been deemed exempt from the MAF restriction.