Gene Variant Curation Core (GVCC)

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PROJECT SUMMARY/ABSTRACT The Gene and Variant Curation Core (GVCC) is a multi-institutional core that will be the central hub for decision making for the genes and variants for study by the Epilepsy Multiplatform Variant Prediction (EpiMVP) projects in this Center Without Walls (CWOW). The core will integrate genetic sequence data from population and patient cohorts, as well as the functional readouts from the EpiMVP projects to develop EpiPred. EpiPred will be an epilepsy-specific computational model that will predict the likelihood of a variant being pathogenic or benign. The core capitalizes on the broad and multifaceted expertise of investigators at five major universities including Northwestern University, Weill Cornell Medical College, University of Michigan, University of California San Francisco and University of Washington. The broad objective of the core is to firstly curate and select genes and variants for study in projects 1-3 of the EpiMVP. This data will be collated from large population databases and patient datasets from our industry partners in the clinical genetic testing industry as well as ClinVar and large consortia sequencing projects. Secondly the GVCC will use prediction tools, protein structural modeling and functional data from projects 1-3 to create and optimize EpiPred, an epilepsy-specific computational model that will predict the likelihood of a variant being pathogenic or benign. Finally, the GVCC will support data management and web-based resources needed for seamless data sharing and implementation of EpiPred in the epilepsy community. The GVCC will work with ClinGen curators and our industry partners to test EpiPred accuracy on variants that are curated independently by the Epilepsy Working Group, allowing refinement of both the algorithm and the criteria used by ClinGen for curation. Eventually, we aim to incorporate the EpiMVP prediction algorithms into ClinGen curation practices, and ultimately the ACMG criteria as well. Moreover, to expand the accessibility of EpiPred for patients, families, healthcare providers and researchers we will establish a web-based version of EpiPred.