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ClinGen Clinical Genome Resource

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 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.
  • 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 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.

Participants

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
  • Participants
    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

Select Working Groups

Working Group

Chairs

Description

Adult Actionability

Adam Buchanan
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

Pediatric Actionability

Jessica E. Hunter, Bradford Powell

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

Ancestry and Diversity

Alice Popejoy,
Kelly Ormond

Investigate how ancestry information is used in clinical genomics and provide guidance for the community about how best to use race, ancestry, and genomics in a way that is scientifically rigorous and ethically responsible

Clinical Domain

Jonathan Berg
Sharon Plon
Heidi Rehm

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

Consent and Disclosures Recommendations Committee (CADRe)


Adam Buchanan,
Miranda Hallquist, 
Kelly Ormond

Develop communication strategies for genetic testing consent and disclosure discussions to improve access to genetic information while maintaining quality patient care

Complex Disease

Katrina Goddard,
Genevieve Wojcik

Define common language for describing complex risk scores and methodology, create guidelines for assessing the quality of complex risk scores in the literature, and provide guidance on complex risk score methodology

Data Platform

Larry Babb,
Aleks Milosavljevic,
Helio Costa

Establish sustainable improvements to realize an integrated system of products greater than the sum of its parts

Education, Coordination, and Training

Danielle Azzariti,
Lisa Kurtz,
Erin Riggs

Foster community engagement in all aspects of ClinGen through education, outreach, training, and resource development

Gene Curation

Jonathan Berg 
Christa Martin

Develop evidence-based methods for evaluating gene-disease associations to support gene curation activities across
ClinGen

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

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

  • Select Working Groups

    Working Group

    Chairs

    Description

    Adult Actionability

    Adam Buchanan
    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

    Pediatric Actionability

    Jessica E. Hunter, Bradford Powell

    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

    Ancestry and Diversity

    Alice Popejoy,
    Kelly Ormond

    Investigate how ancestry information is used in clinical genomics and provide guidance for the community about how best to use race, ancestry, and genomics in a way that is scientifically rigorous and ethically responsible

    Clinical Domain

    Jonathan Berg
    Sharon Plon
    Heidi Rehm

    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

    Consent and Disclosures Recommendations Committee (CADRe)


    Adam Buchanan,
    Miranda Hallquist, 
    Kelly Ormond

    Develop communication strategies for genetic testing consent and disclosure discussions to improve access to genetic information while maintaining quality patient care

    Complex Disease

    Katrina Goddard,
    Genevieve Wojcik

    Define common language for describing complex risk scores and methodology, create guidelines for assessing the quality of complex risk scores in the literature, and provide guidance on complex risk score methodology

    Data Platform

    Larry Babb,
    Aleks Milosavljevic,
    Helio Costa

    Establish sustainable improvements to realize an integrated system of products greater than the sum of its parts

    Education, Coordination, and Training

    Danielle Azzariti,
    Lisa Kurtz,
    Erin Riggs

    Foster community engagement in all aspects of ClinGen through education, outreach, training, and resource development

    Gene Curation

    Jonathan Berg 
    Christa Martin

    Develop evidence-based methods for evaluating gene-disease associations to support gene curation activities across
    ClinGen

    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

    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

Tools and Resources

Resource

Description

GenomeConnect

ClinGen’s online patient registry that securely shares genetic and health information

ClinGen Allele Registry (CAR)

Search interface that provides unique variant identifiers programmatically (via APIs).

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.

  • Tools and Resources

    Resource

    Description

    GenomeConnect

    ClinGen’s online patient registry that securely shares genetic and health information

    ClinGen Allele Registry (CAR)

    Search interface that provides unique variant identifiers programmatically (via APIs).

    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. 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.

Glingen diagram

  • 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. 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.

    Glingen diagram

Publications

For a full list of publications, please visit ClinicalGenome.org.

  • Milko LV, Funke BH, Hershberger RE, Azzariti DR, Lee K, Riggs ER, Rivera-Munoz EA, Weaver MA, Niehaus A, Currey E, Craigen WJ, Mao R, Offit K, Steiner RD, Martin CL, Rehm HL, Watson MS, Ramos EM, Plon SE, Berg JS. Development of Clinical Domain Working Groups for the Clinical Genome Resource (ClinGen): lessons learned and plans for the future. Genetics in Medicine. September 2018. [Genetics in Medicine]
     
  • Rehm HL, Berg JS, Plon SE. ClinGen and ClinVar - Enabling Genomics in Precision Medicine. Human Mutation. 2018; 39: 1473 - 1475. [Wiley]
     
  • Strande NT, Riggs ER, Buchanan AH, Ozge CB, DiStefano M, Dwight SS, Goldstein J, Ghosh Rajarshi, Seifert BA, Sneddon TP, Wright MW, Milko LV, Cherry M, Giovanni MA, Murray MF, O’Daniel JM, Ramos EM, Santani AB, Scott AF, Plon SE, Rehm HL, Martin CL, Berg JS. Evaulating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource. Am J Hum Genet. June 2017. [PubMed]
     
  • Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Marin CL, Nussbaum RL, Plon SE, Ramos EM, Sherry ST, Watson MS. ClinGen - The Clinical Genome Resource. N Engl J Med. June 2014. [N Engl J Med]
  • Publications

    For a full list of publications, please visit ClinicalGenome.org.

    • Milko LV, Funke BH, Hershberger RE, Azzariti DR, Lee K, Riggs ER, Rivera-Munoz EA, Weaver MA, Niehaus A, Currey E, Craigen WJ, Mao R, Offit K, Steiner RD, Martin CL, Rehm HL, Watson MS, Ramos EM, Plon SE, Berg JS. Development of Clinical Domain Working Groups for the Clinical Genome Resource (ClinGen): lessons learned and plans for the future. Genetics in Medicine. September 2018. [Genetics in Medicine]
       
    • Rehm HL, Berg JS, Plon SE. ClinGen and ClinVar - Enabling Genomics in Precision Medicine. Human Mutation. 2018; 39: 1473 - 1475. [Wiley]
       
    • Strande NT, Riggs ER, Buchanan AH, Ozge CB, DiStefano M, Dwight SS, Goldstein J, Ghosh Rajarshi, Seifert BA, Sneddon TP, Wright MW, Milko LV, Cherry M, Giovanni MA, Murray MF, O’Daniel JM, Ramos EM, Santani AB, Scott AF, Plon SE, Rehm HL, Martin CL, Berg JS. Evaulating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource. Am J Hum Genet. June 2017. [PubMed]
       
    • Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Marin CL, Nussbaum RL, Plon SE, Ramos EM, Sherry ST, Watson MS. ClinGen - The Clinical Genome Resource. N Engl J Med. June 2014. [N Engl J Med]

Funding Opportunities

Program Staff

NHGRI Program Directors

Erin M. Ramos, Ph.D., M.P.H.
Erin M. Ramos, Ph.D., M.P.H.
  • Program Director
  • Division of Genomic Medicine
Ken Wiley, Jr., Ph.D.
Ken Wiley Jr, Ph.D.
  • Program Director
  • Division of Genomic Medicine
Nicole C. Lockhart, Ph.D.
Nicole C. Lockhart, Ph.D.
  • Health Sciences Administrator
  • Division of Genomics and Society

NHGRI Program Analysts

Natalie Pino
Natalie Pino
  • Scientific Program Analyst
  • Division of Genome Sciences
Julie Kim
Julie Kim
  • Scientific Program Analyst
  • Division of Genome Sciences

Other Institutes

Generic Profile Photo
Danuta Krotoski, Ph.D.
  • Program Director
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
Generic Profile Photo
Andrew N. Freedman, Ph.D.
  • Chief
  • Clinical and Translational Epidemiology Branch, National Cancer Institute
Generic Profile Photo
Kelly K. Filipski, Ph.D., M.P.H.
  • Program Director
  • Clinical and Translational Epidemiology Branch, National Cancer Institute

Last updated: October 9, 2019