The Clinical Genome (ClinGen) Resource

ClinGen collects phenotypic and clinical information on variants across the genome, develop a consensus approach to identify clinically relevant genetic variants, and disseminate information about the variants to researchers and clinicians. The resource will advance genomics in clinical care and improve our understanding of phenotypic and functional effects of genetic variants and their clinical value.

Background

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 through centralized databases for clinical and research use.
Standardize clinical annotation and interpretation of variants.
Improve understanding of variation in diverse populations.
Develop machine-learning algorithms to improve the throughput of variant interpretation.
Implement evidence-based expert consensus for curation of clinical validity.
Assess the 'medical actionability' of genes and variants to support their use in clinical care systems
Disseminate the collective knowledge/resources and ensure EHR interoperability.

Participants

The following groups are receiving grants:

Heidi L. Rehm, Broad Institute; David H. Ledbetter and Christa L. Martin, Geisinger Health System;
This group is developing standard formats for gathering and depositing data into ClinVar. It will work with clinical laboratories and with specific gene databases to facilitate their submissions to ClinVar and to reduce discrepancies in variant classification. They have also created GenomeConnect, a patient registry, to help people share de-identified genetic and health information with researchers and connect them with other patients.

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, and pediatric neurology to focus on evaluating variants for clinical relevance.
Carlos D. Bustamante, Stanford University and Sharon E. Plon, Baylor College of Medicine.
This group is working closely with the other grants to develop a robust curation interface to analyze the clinical validity of gene-disease associations and implement the ACMG-AMP guidelines for interpreting sequence variants. Additionally, the team is developing various software products to assist variant curation efforts, such as a Pathogenicity Calculator, which generates assertions automatically based on a set of evidence provided, and an Allele Registry to create and maintain a unique allele ID. Lastly, they are developing the Case Level Evidence Aggregation and Reporting Network (CLEARNET), a scalable resource for aggregating case-level data in the cloud for use in curation

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

Working Groups

Working Group	Chairs	Description	Contact
Actionability	Jim Evans Katrina Goddard	Identify those human genes that, when significantly altered, confer a high risk of serious disease that could be prevented or mitigated if the risk were known	Kristy Lee
Clinical Domain	Jonathan Berg Sharon Plon	Enlist representatives from community-organized efforts to implement standardized protocols for gene or sequence variant specific annotations of genes related to the specific disease domain	Laura Milko Meredith Weaver
Consent and Disclosures Recommendations Committee (CADRe)	Andy Faucett, Kelly Ormond	Explore the ethical, legal, and social (ELSI) issues relating to reporting the actionability of particular genes/variants in the clinical care process	CLINGEN_ELSI@list.nih.gov
Data Exchange	Larry Babb Chris Bizon Tristan Nelson	Provide consistent representation of the information housed in ClinGen resources and facilitate ClinGen GA4GH Driver Project	Danielle Azzariti
Education	Danielle Azzariti Erin Riggs	Foster community engagement in all aspects of the ClinGen project through education, outreach, and resource development	CLINGEN_EDUCATION@list.nih.gov
Gene Curation	Jonathan Berg Christa Martin	Develop evidence-based methods for evaluating gene-disease associations to support gene curation activities across the ClinGen project	Laura Milko Erin Riggs
Genomic Variant	Christa Martin Sharon Plon Heidi Rehm	Develop variant classification and curation standards and facilitate the submission of sequence and structural variants to ClinVar	Danielle Azzariti Erin Riggs
Sequence Variant Interpretation	Leslie Biesecker Steven Harrison	Support the refinement and evolution of the ACMG/AMP Interpreting Sequence Variant Guidelines to develop quantitative approaches to variant interpretation	Danielle Azzariti
Steering Committee	Katrina Goddard	Provide oversight and guidance and make executive decisions to ensure ClinGen reaches its goals	CLINGEN_EXEC@list.nih.gov

Software and Tools

Software Product	Description
ClinGen Allele Registry (CAR)	The CAR provides unique variant identifiers both programmatically (via APIs) and via this search interface.
Variant Curation Interface	The ClinGen variant curation process combines clinical, genetic, population, and functional evidence with expert review to classify variants into 1 of 5 categories according to the ACMG guidelines .
Pathogenicity Calculator	To enable wide application of the ACMG/AMP and similar guidelines and the development of collective knowledge by the community, ClinGen has developed the ClinGen Pathogenicity Calculator.
Gene Curation Interface	The ClinGen gene curation process combines an appraisal of genetic and experimental data in the scientific literature with expert review to classify gene-disease pairs into 1 of 6 categories according to ClinGen's Gene-Disease Clinical Validity Classification framework.
Actionability Curation Interface	ClinGen Actionability Working Group aims to identify those human genes that, when significantly altered, confer a high risk of serious disease that could be prevented or mitigated if the risk were known.
Data Exchange	The ClinGen Data Exchange is a comprised of the platform, data models and tools that enable an environment of standardized exchange of genomic knowledge.

ClinGen and ClinVar Partnership

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.

Glingen diagram

Publications

Gelb BD, Cavé H, Dillon MW, Gripp KW, Lee JA, Mason-Suares H, Rauen KA, Williams B, Zenker M, Vincent LM8. RASopathy Expert Panel consensus methods for variant interpretation. Genetics in Medicine. March 2018. [PubMed]

Tavtigian SV, Greenblatt MS, Harrison SM, Nussbaum RL, Prabhu SA, Boucher KM, Biesecker LG. Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. Genetics in Medicine. January 2018. [PubMed]

Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, Jongbloed JDH, Macaya D, Manrai A, Orland K, Richard G, Spoonamore K, Thomas M, Thomson K, Vincent LM, Walsh R, Watkins H, Whiffin N, Ingles J, van Tintelen JP, Semsarian C, Ware JS, Hershberger R, Funke B. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel. Genetics in Medicine. March 2018. [PubMed]