The Clinical Genome (ClinGen) Resource

Medical and research centers are increasingly sequencing exomes or whole genomes of patients. However, identifying sequence variants relevant to disease is difficult. As a result, information on few genomic variants is used in clinical practice. One factor that limits the clinical use of variant information is the lack of an openly accessible knowledge base that captures genetic variants, their phenotypic and functional effects, and other clinical information

ClinGen investigators are developing standard approaches for sharing genomic and phenotypic data provided by clinicians, researchers, and patients through centralized databases, such as ClinVar, and are working to standardize the clinical annotation and interpretation of genomic variants. Working groups are implementing evidence-based expert consensus methods to curate the clinical validity and medical actionability of genes and variants. Experts in the areas of cardiovascular disease, pharmacogenomics, hereditary (germline) cancer, somatic cancer, and inborn errors of metabolism have been brought together to assist in these curation efforts. ClinGen also aims to develop machine-learning algorithms to improve the throughput of variant interpretation and to improve understanding of variation in diverse populations as it relates to interpreting genetic test results. Lastly, ClinGen will disseminate the collective knowledge and resources for unrestricted use in the community and for use in EHR ecosystems.

Goals of ClinGen

• Share genomic and phenotypic data between clinicians, researchers, and patients through centralized and federated databases for clinical and research use.
• Develop and implement standards to support clinical annotation and interpretation of genes and variants.
• Develop data standards, software infrastructure and computational approaches to enable curation at scale and facilitate integration into healthcare delivery.
• Enhance and accelerate expert review of the clinical relevance of genes and variants.
• Disseminate and integrate ClinGen knowledge and resources to the broader community.

The following groups are receiving grants:

• Heidi L. Rehm, Broad Institute; David H. Ledbetter and Christa L. Martin, Geisinger Health System
  A primary focus of this group is advocating for and facilitating submission of clinical-grade variant interpretations into NCBI’s publicly available ClinVar database. This group works with clinical laboratories, patients and advocacy groups (through their GenomeConnect registry),and other stakeholders in the medical genetics community to advance clinical data sharing. Additionally, this group is focused on gene and variant curation through expert panels within the hearing loss, neurodevelopmental, RASopathy and skeletal dysplasia clinical domains as well as resolving differences in variant interpretation working directly with clinical laboratories. The Broad/Geisinger grant is also leading efforts to update the copy number and sequence variant interpretation guidelines in collaboration with ACMG. This group also co-chairs the Data Platform WG along with the other ClinGen groups, working towards standardization and sharing of genomic data, evidence and clinical assertions of genes and variants.
   

• Jonathan S. Berg, University of North Carolina Chapel Hill; Marc Williams, Geisinger Health System; Michael S. Watson, American College of Medical Genetics and Genomics; Katrina Goddard, Kaiser Permanente.
  This group is defining categories of clinical relevance and medical actionability for genes and variants. They have organized clinical domain working groups with experts in hereditary (germline) cancer, somatic cancer, cardiovascular disease, inborn errors of metabolism, neuromuscular disorders, hemostasis and thrombosis, and ophthalmology to focus on evaluating variants for clinical relevance.
   

• Thomas Montine, Stanford University and Sharon E. Plon, Baylor College of Medicine
  This group is working closely with the other grants to develop a series of web-accessible tools and robust curation interfaces to support the ClinGen gene curation, actionability and variant curation per the ACMG/AMP guideline activities. The Stanford and Baylor teams work with various stakeholders to routinely update the software with features that streamline and improve curation workflows that adhere to data privacy standards. In addition to the curation interfaces, other tools include the ClinGen Allele Registry, Linked Data Hub, and the Evidence Repository to display structured evidence. This team also supports clinical domain working groups in hereditary (germline) cancer, somatic cancer, and cardiovascular disease. Finally, they support efforts to establish standards in the use of ancestry and diversity information in clinical genomics and complex (eg. polygenic) disease score reporting.
   

The following individuals are part of the External Scientific Panel:

• Rex Chisholm, Northwestern University - Chair
• Debra Leonard, University of Vermont
• John Carpten, Translational Genomics Research Institute
• Holly Peay, Parent Project Muscular Dystrophy
• Peter Tarczy-Hornoch, University of Washington
• Richard Sharp, Cleveland Clinic
• Georgia L. Weisner, Vanderbilt University Medical Center

ClinVar and ClinGen, two NIH-based efforts, have formed a critical partnership to improve our knowledge of clinically relevant genomic variation. This partnership includes significant efforts in data sharing, data archiving, and collaborative curation to characterize and disseminate the clinical relevance of genomic variation. ClinGen relies on ClinVar as a source for existing data on variants, which are submitted to ClinVar from diverse sources. ClinGen Expert Panels review the data on these variants and submit their standardized interpretations to ClinVar as expert-reviewed records.