Reactive gene curation to support interpretation and reporting of a clinical genome test for rare disease: Experience from over 1,000 cases

Current standards in clinical genetics recognize the need to establish the validity of gene-disease relationships as a first step in the interpretation of sequence variants. We describe our experience incorporating the ClinGen Gene-Disease Clinical Validity framework in our interpretation and reporting workflow for a clinical genome sequencing (cGS) test for individuals with rare and undiagnosed genetic diseases. This “reactive” gene curation is completed upon identification of candidate variants during active case analysis and within the test turn-around time by focusing on the most impactful evidence and taking advantage of the broad applicability of the framework to cover a wide range of disease areas. We demonstrate that reactive gene curation can be successfully implemented in support of cGS in a clinical laboratory environment, enabling robust clinical decision making and allowing all variants to be fully and appropriately considered and their clinical significance confidently interpreted. [Display omitted] •Evaluation of gene-disease relationships is essential for variant interpretation•Experience using reactive gene curation to support a clinical genome test•Rigorous reactive gene curation enables robust clinical decision making Clause et al. describe a clinical laboratory’s experience implementing reactive evaluation of gene-disease relationships within the interpretation and reporting workflow of a clinical genome sequencing test for rare genetic diseases. This work demonstrates that rigorous, reactive gene curation aids in variant interpretation and meets a critical need for clinical reporting.