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NIH

The Clinical Genome (ClinGen) Resource

ClinGen logo

 

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. The Clinical Genome Resource (ClinGen) aims to collect 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.  This resource is essential for advancing the goals of implementing genomics in clinical care and will improve the understanding of phenotypic and functional effects of genetic variants and their clinical value.
 
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.

ClinGen Principal Investigators and Their Roles in the ClinGen Consortium

 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.

ClinGen Working Groups

Working Group Chairs Description Contact
Genomic Variation


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
(dazzariti@partners.org
& Erin Riggs
(eriggs@geisinger.edu)
 
Phenotyping
David Miller
 
Develops approaches for the standardization and enhanced collection of phenotypic data for annotating genetic variants
Juliann Koenig
(jkoenig@geisinger.edu)
 
Data Modeling Larry Babb
Provide a common set of definitions and consistent representation of core concepts, attributes and terminology to support ClinGen and harmonize with relevant standards efforts.
and terminology, and consistency
 
Danielle Azzariti
(dazzariti@partners.org)
Informatics and Analysis Carlos Bustamante
Coordinate the acquisition, analysis, and
dissemination of ClinGen resource data
Cody Sam
(codysam@stanford.edu)
 
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 (laura_milko@med.unc.edu & eriggs@geisinger.edu)
 
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
(kristy_lee@med.unc.edu)
Somatic Cancer Clinical Domain WG Subha Madhavan, Shashi Kulkarni Coming Soon
Meredith Weaver
(mweaver@ACMG.NET)

 
Hereditary (Germline) Cancer Clinical Domain WG Matthew Ferber, Ken Offit, Sharon Plon Centralize and curate genetic knowledge in order to develop guidance for molecular diagnostic germline cancer testing Kristy Lee
(kristy_lee@med.unc.edu)
Cardio-vascular Disease Clinical Domain WG Euan Ashley, Birgit Funke, Ray Hershberger Create a comprehensive, standardized knowledge base of genes and variants relevant for cardiovascular genetic and genomic medicine Laura Milko
(laura_milko@med.unc.edu)
Inborn Errors of Metabolism Clinical Domain WG Rong Mao, Robert Steiner, William Craigen Create a comprehensive, standardized knowledge base of genes and variants relevant for metabolic diseases and genomic medicine Meredith Weaver
(mweaver@ACMG.NET)
Pharmaco-genomics Clinical Domain WG Teri Klein, Howard McLeod Integrate knowledge about human genetic variation
to inform drug response

Andy Rivera
(andy_rivera@MED.UNC.EDU

Education, Engagement and Counseling Andy Faucett,
Erin Riggs
 
Foster community engagement in all aspects of the ClinGen project through education, outreach, and resource development Erin Riggs
(eriggs@geisinger.edu)
 
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
 
Miranda Hallquist (mhallquist@geisinger.edu)
EHR Integration Marc Williams
Ensure that the ClinGen resource is designed to be accessible to providers and patients through
electronic health record and related systems
 

Meredith Weaver
(mweaver@ACMG.NET)
 
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. For more information visit https://www.clinicalgenome.org/about/about-the-clingen-and-clinvar-partnership/.

Patients, clinicians, labs, researchers sharing genetic and health data - Clingen's critical questions - Is this gene associated with a disease? Is this variant causative? Is this information actionable? - Building a genomic knowledge base - Improved patient care through genomic medicine

Key ClinGen 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.

 

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

Funding Announcements

RFA-HG-12-016:  Clinically Relevant Genetic Variants Resource: A Unified Approach for Identifying Genetic Variants for Clinical Use (U01)

PAR-14-191: Genomic Resource Grants for Community Resource Projects (U41)
*NHGRI recently switched to using the U24 for the Genomic Resource Grants, but the ClinGen Applications were submitted under the U41 PAR.

News Releases

FDA takes new action to advance the development of reliable and beneficial genetic tests that can improve patient care [fda.gov]
December 4, 2018

Resources

Websites
ClinGen Website: http://clinicalgenome.org/ 
ClinAction Workshop:  http://www.genome.gov/27546546/clinaction-agenda-powerpoints-and-videos/
ClinVar: http://www.ncbi.nlm.nih.gov/clinvar/
GenomeConnect: http://clinicalgenome.org/genomeconnect/for-participants/
Papers

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]

Contacts

Program Directors

Erin Ramos, Ph.D., M.P.H. (Lead Program Director)
Lisa Brooks, Ph.D.
Ken Wiley, Ph.D.
Nicole Lockhart, Ph.D.

Program Analysts

Robert Fullem, NHGRI
Natalie Pino, NHGRI

Other IC Funding

Danuta Krotoski, NICHD
Andy Freedman, NCI
Kelly Filipski, NCI

Last Updated: December 4, 2018