The Clinical Genome (ClinGen) Resource

ClinGen collects phenotypic and clinical information on variants across the genome, develops consensus approaches to identifying their clinical relevance, and disseminates this information to researchers and clinicians. The resource will advance genomics in clinical care and improve our understanding of the phenotypic and functional effects of genetic variants and their clinical value.

Publications
Funding Opportunities
Resources
Program Staff
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Background

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.

Background
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.

Participants

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

Participants
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

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 Carlos Bustamante	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	Carlos Bustamante 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
Data Access, Privacy, and Confidentiality	Alice Popejoy	Manage data policy frameworks for ClinGen that respond to the needs of an evolving curation ecosystem
Education, Coordination, and Training	Danielle Azzariti Erin Riggs	Foster community engagement in all aspects of ClinGen through education, outreach, training, and resource development
Gene Curation	Erin Riggs Courtney Thaxton	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 Carlos Bustamante	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	Carlos Bustamante 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
Data Access, Privacy, and Confidentiality	Alice Popejoy	Manage data policy frameworks for ClinGen that respond to the needs of an evolving curation ecosystem
Education, Coordination, and Training	Danielle Azzariti Erin Riggs	Foster community engagement in all aspects of ClinGen through education, outreach, training, and resource development
Gene Curation	Erin Riggs Courtney Thaxton	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.
Evidence Repository	The ClinGen Evidence Repository provides access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants.

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.
Evidence Repository	The ClinGen Evidence Repository provides access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants.

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.

Publications

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

Popejoy AB, Crooks KR, Fullerton SM, Hindorff LA, Hooker GW, Koenig BA, Pino N, Ramos EM, Ritter DI, Wand H, Wright MW, Yudell M, Zou JY, Plon SE, Bustamante CD, Ormond KE; Clinical Genome Resource (ClinGen) Ancestry and Diversity Working Group. Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures. Am J Hum Genet. July 2020. [PubMed]
McCormick EM, Lott MT, Dulik MC, Shen L, Attimonelli M, Vitale O, Karaa A, Bai R, Pineda-Alvarez DE, Singh LN, Stanley CM, Wong S, Bhardwaj A, Merkurjev D, Mao R, Sondheimer N, Zhang S, Procaccio V, Wallace DC, Gai X, Falk MJ. Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation. Hum Mutation. November 2020. [PubMed]
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.

Popejoy AB, Crooks KR, Fullerton SM, Hindorff LA, Hooker GW, Koenig BA, Pino N, Ramos EM, Ritter DI, Wand H, Wright MW, Yudell M, Zou JY, Plon SE, Bustamante CD, Ormond KE; Clinical Genome Resource (ClinGen) Ancestry and Diversity Working Group. Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures. Am J Hum Genet. July 2020. [PubMed]

McCormick EM, Lott MT, Dulik MC, Shen L, Attimonelli M, Vitale O, Karaa A, Bai R, Pineda-Alvarez DE, Singh LN, Stanley CM, Wong S, Bhardwaj A, Merkurjev D, Mao R, Sondheimer N, Zhang S, Procaccio V, Wallace DC, Gai X, Falk MJ. Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation. Hum Mutation. November 2020. [PubMed]

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]