ClinGen & ClinVar Partnership

ClinVar and ClinGen Partnership

I. INTRODUCTION

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.

ClinVar

  • ClinVar is an archival database that aggregates information about genomic variation and its relationship to human health.
  • ClinVar is funded by the Intramural Research Program of the NIH, National Library of Medicine.
  • Key ClinVar facts:
    • ClinVar is fully public and freely available.
    • ClinVar is a submission-driven database that holds both primary submissions and expert-curated submissions. The scope of the submission may be as small as a single variant.
    • ClinVar welcomes submissions from clinical testing labs, researchers, locus-specific databases, expert panels, and professional societies.
    • ClinVar adds value to submitted interpretations by standardizing descriptions of variants, conditions, and terms for clinical significance.
      • Variants are mapped to reference sequences and reported in HGVS.
      • Conditions are mapped to concepts in MedGen.
      • Clinical significance terms for Mendelian disorders are reported by ACMG categories.
    • More information on ClinVar is available at www.ncbi.nlm.nih.gov/clinvar.

The Clinical Genome Resource (ClinGen)

  • ClinGen aims to create an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research.

  • ClinGen is primarily funded by the National Human Genome Research Institute (NHGRI), through the following three grants: Baylor/Stanford U24HG009649, Broad/Geisinger U24HG006834, UNC U24HG009650.

  • ClinVar is supported by the Intramural Research Program of the NIH, National Library of Medicine.

  • ClinGen Goals:

    • 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.

II. THE CLINGEN AND CLINVAR PARTNERSHIP

When communicating the extremely close working relationship between ClinGen and ClinVar to researchers, clinicians, and the broader public, it is important to be clear and consistent. The following points should be highlighted:

  • ClinGen and ClinVar are close partners and have established a collaborative working relationship. ClinVar has two members on ClinGen’s Steering Committee (Melissa Landrum and  Brandi Kattman) and other NCBI staff participate in various ClinGen Working Groups.
  • ClinGen and ClinVar goals are aligned and both projects play a critical role in the growing data sharing movement within the clinical genetics community.
  • ClinVar is a critical resource for ClinGen. It serves as the primary site for deposition and retrieval of variant data and annotations from individual submitters.
  • ClinGen relies on ClinVar as a source for existing data on variants, which are submitted to ClinVar from diverse sources. ClinGen Expert Panels review data in ClinVar to as part of the variant curation process and submit their own classifications to ClinVar as expert-reviewed records.
  • ClinGen is providing input to ClinVar on the structure and layout of the database that is instrumental to its development. However, ClinVar is not subsumed by ClinGen and aims to develop a database and interface that are responsive to all potential users.
  • Specific ways in which the two groups are working together:
    • ClinGen provides recommendations to ClinVar related to the underlying data structure and user interface.
    • ClinGen devotes resources to facilitate data submission into ClinVar by soliciting new submissions from many sources as well as working closely with many clinical testing labs and other submitters to map their data to ClinVar fields and structure their submissions in the proper format.
    • The two groups worked closely to develop a star system to define the review level of a submission. This system was launched in ClinVar in July 2015.
    • ClinGen reviews Expert Panel applications and approves groups to submit to ClinVar as an Expert Panel. 
    • ClinGen and NHGRI leadership contributed to the development of ClinVar submission policies and have provided guidance regarding identifiability concerns.
    • ClinVar contributes expertise in numerous areas including development and use of data schemas and ontologies, and appropriate linkages to relevant NCBI resources.

III. PROCESS FOR REQUESTING CLINVAR MODIFICATIONS

ClinGen and ClinVar work very closely to ensure that the underlying data structure and user interface of ClinVar are clear, transparent, and receptive to the needs of the clinical genetics community. ClinGen and ClinVar hold two focused workings calls a month and a larger “ClinVar Community” call with interested members of the community to discuss any proposed changes and gather feedback.

  • Straightforward recommendations that both groups agree upon during a Working Group (WG) call will be immediately added to the NCBI JIRA queue for tracking and processing.
  • Recommendations that require deeper consideration by ClinVar will be flagged for additional discussion on a future WG call. This ensures adequate time to carefully consider the impact of proposed modifications. Both groups will return to a future call with a fleshed out proposal and discussion will follow. If consensus is reached the proposal will be added to the JIRA queue.
  • Recommendations that have a significant impact on ClinVar may be presented to NCBI’s leadership and/or to the Medical Genetics Working Group of their Board of Scientific Counselors (https://www.ncbi.nlm.nih.gov/home/about/bosc/) for additional input before a decision is made.