MODIFIED ABSTRACT Genomic discovery is moving rapidly from genotyping approaches to large scale sequencing studies to capture the full breadth of genetic variation. Our proposal to create a Central Sequencing and Genotyping (CSG) facility combines key strengths of two leading laboratories in the clinical genomics space, the Partners Laboratory for Molecular Medicine (LMM) and the Broad Institute. Together, we propose to (a) create a seamless CLIA-grade process for generating and interpreting genomic sequence data for eMERGE III, (b) to return clinically interpreted results to eMERGE sites and (c) provide infrastructure to manage these results over time as new information emerges. In addition, raw data and annotations will be transferred to the eMERGE Coordinating Center (CC) and/or deposited in a portal housed and managed by Baylor College of Medicine to enable aggregate data analyses for novel discoveries. This proposal capitalizes on the Broad Institute's expertise in high throughput genomic sequencing and data analysis and on LMM's expertise in clinical genomic result interpretation as well as its knowledge management infrastructure and experience in returning clinical reports and knowledge updates to providers. LMM's genetic knowledge base is housed by GeneInsight Lab (GIL), as well as GeneInsight Clinic (GIC), an application that supports electronic return of results, automated patient specific clinical knowledge updates and options for electronic health record (EHR) integration. The PIs of this application are members of other NHGRI consortia and organizations developing standards in genomics, which will facilitate rapid and seamless exchange of best practices to support the translation of genomics into medical practice.