The Clinical Genome (ClinGen) Resource

Medical and research centers are increasingly sequencing patient exomes and genomes. However, it is difficult to identify which sequence variants are relevant to disease. As a result, information on only a few genomic variants is used in clinical practice. One factor that limits the clinical use of variant information is the lack of openly accessible knowledge bases that capture 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. In December 2018, the FDA recognized ClinGen’s hereditary germline variant curations as a valid source of accurate human variant interpretation data. ClinGen also aims 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.
• Embrace diversity in all aspects from diversity of the genomics workforce to the diversity of the patients and population databases.
• Disseminate and integrate ClinGen knowledge and resources to the broader community, engaging patients, healthcare systems, scientific experts and genetics professionals.

The following groups are receiving grants:

• Heidi L. Rehm, Broad Institute
  Christa L. Martin, Geisinger Health System
  
  A major focus of this grant is advocating for and facilitating submission of clinical-grade variant interpretations into NCBI’s publicly available ClinVar database and sharing gene-level interpretations through GenCC. 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, skeletal and kidney clinical domains as well as resolving differences in variant interpretation working directly with clinical laboratories. The Broad/Geisinger grant has also led efforts to update the copy number and sequence variant interpretation guidelines in collaboration with ACMG. This group also develops solutions to facilitate data exchange within the ClinGen ecosystem and with the broader community. This team also works with standards bodies including GA4GH and HL7 Clinical Genomics WG to develop standards for genomic knowledge sharing, including evidence and clinical assertions of genes and variants.

• Jonathan S. Berg, University of North Carolina Chapel Hill
  Katrina Goddard, Kaiser Permanente
  Marc Williams, Geisinger Health System
  
  This group plays a leading role in organizing the ClinGen curation ecosystem, focusing on clinical domain working groups with expertise in cardiovascular disease, inborn errors of metabolism, somatic cancer, neuromuscular disorders, hemostasis and thrombosis, immunology, and ocular disorders.  The team has been integral to the development of evidence frameworks and standard operating procedures for evaluating the clinical relevance and actionability of genes and variants. In conjunction with this effort, they are organizing, overseeing, and expanding the expert curation ecosystem to increase the workforce that is performing the evaluations. They are concurrently engaging various stakeholders to increase the community workforce. The Adult and Pediatric Actionability work groups, led by the Kaiser team, develop reports to help policy makers, laboratorians, researchers, and providers understand the current actionability guidelines in patient populations. The UNC/Kaiser group is committed to using evaluation and needs assessment methods to solicit feedback from end users and to improve curation tools based on that feedback. Lastly, this group is developing education modules so that medical geneticists and genetic counselors can obtain continuing education credits for the curation-related work they are performing.

• Thomas Montine, Stanford University
  Sharon E. Plon, Baylor College of Medicine
  
  This group develops web-accessible tools and robust curation interfaces to support the ClinGen actionability curation and gene/variant curation per the ACMG/AMP guidelines, including the Variant Curation Interface, Gene Curation Interface, and Actionability Curation Interface. They routinely update and extend the software with features that streamline and improve curation workflows, and maintain compliance as the first FDA-Recognized Human Genetic Variant Database. 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 supports multiple working groups in hereditary (germline) cancer and works with the UNC team on Somatic Cancer.  In addition, they lead efforts in the establishment of standards in the use of ancestry and diversity information in clinical genomics and complex (eg. polygenic) disease score reporting. Finally, they are active in educational training and involvement in ClinGen, with a focus on outreach and diversity in clinical genomics. 

The following individuals are part of the External Scientific Panel:

• Rex Chisholm, Northwestern University - Chair
• Debra Leonard, University of Vermont
• John Carpten, University of Southern California
• Holly Peay, RTI International
• Peter Tarczy-Hornoch, University of Washington
• Richard Sharp, Mayo 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.

• ClinGen
• GenomeConnect
• ClinVar