The centralization of human genomic variation data is a critical step in accelerating genomic medicine. The creation of a single, unified database of genome-wide structural and sequence-level variation will not only enable more efficient approaches to data analysis, but will also ensure the use of a uniform set of standards across clinical and research applications. The success of such a database has already been demonstrated for structural variation with this group's ongoing effort, the International Standards for Cytogenomic Arrays (ISCA) Consortium, which has made major advances in establishing resources for data analysis and interpretation. To address the critical need to expand this effort to genome-wide sequence-level variation and to unite variation data within a single resource, the following Specific Aims are proposed;1) Develop a standardized infrastructure for data acquisition, submission and public access for a clinical genomic variation database. 2) Coordinate the submission of variant and phenotypic data into ClinVar, a unified database at the National Center for Biotechnology Information (NCBI). 3) Implement sustainable expert clinical level curation systems for human genomic variants. Recognizing that their ability to standardize the clinical interpretation of variants will be much improved if larger bodies of data are availabl, many clinical laboratories in the US have already agreed to provide access to their data for this project. Access to all data and evidence on human genomic variants will be maintained within the ClinVar database, and the state of variant understanding will be graded, allowing components of the centralized database to be used for different applications, from clinical decision support to basic science research. A centralized database will also allow us to harness the collective experience of multiple laboratories to support evidence-based curation of structural and sequence-level variants leading to a clinical grade database of genome-wide variation. This innovative project will create a resource that can be used for a variety of applications, providing valuable data for the day-to-day interpretation of clinical laboratory results, for research investigations, and for the development of guidelines surrounding the use of genetic information in clinical care.

Public Health Relevance

Hundreds of thousands of disease-causing variants have been identified in patients with disease, yet only a small fraction of that data, and the interpretation of it, is accessible to researchers and clinicians. This project will serve to collect and organize genomic data from many sources into a free and publically accessible environment and enable expert curation of that data for use in improving healthcare and biomedical research.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Biotechnology Resource Cooperative Agreements (U41)
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Brooks, Lisa
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Brigham and Women's Hospital
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Amendola, Laura M; Jarvik, Gail P; Leo, Michael C et al. (2016) Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet 98:1067-76
Garber, Kathryn B; Vincent, Lisa M; Alexander, John J et al. (2016) Reassessment of Genomic Sequence Variation to Harmonize Interpretation for Personalized Medicine. Am J Hum Genet 99:1140-1149
Goodwin, Gregory; Hawley, Pamela P; Miller, David T (2016) A Case of HDR Syndrome and Ichthyosis: Dual Diagnosis by Whole-Genome Sequencing of Novel Mutations in GATA3 and STS Genes. J Clin Endocrinol Metab 101:837-40
Ritter, Deborah I; Roychowdhury, Sameek; Roy, Angshumoy et al. (2016) Somatic cancer variant curation and harmonization through consensus minimum variant level data. Genome Med 8:117
O'Daniel, Julianne M; McLaughlin, Heather M; Amendola, Laura M et al. (2016) A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories. Genet Med :
Green, Robert C; Goddard, Katrina A B; Jarvik, Gail P et al. (2016) Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine. Am J Hum Genet 98:1051-66
Rehm, Heidi L; Hynes, Elizabeth; Funke, Birgit H (2016) The Changing Landscape of Molecular Diagnostic Testing: Implications for Academic Medical Centers. J Pers Med 6:
Hunter, Jessica Ezzell; Irving, Stephanie A; Biesecker, Leslie G et al. (2016) A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation. Genet Med 18:1258-1268
Delaney, Susan K; Hultner, Michael L; Jacob, Howard J et al. (2016) Toward clinical genomics in everyday medicine: perspectives and recommendations. Expert Rev Mol Diagn 16:521-32
Shen, Lishuang; Diroma, Maria Angela; Gonzalez, Michael et al. (2016) MSeqDR: A Centralized Knowledge Repository and Bioinformatics Web Resource to Facilitate Genomic Investigations in Mitochondrial Disease. Hum Mutat 37:540-8

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