Posts A Report About Clinical Genome(ClinGen) Resource

A Report About Clinical Genome(ClinGen) Resource

Basic Information

Report: Clinical Genome (ClinGen) Resource - Erin Ramos and Sharon Plon

Why we want the ClinGen Resource

  • 检测突变的能力大大超过将这些突变与临床影响建立解释的能力
  • often without common data standards and approaches for interpretation
  • Clinical Testing Lab Databases: Largely absent from public domain

The ClinGen Program

Increase data sharing and build an authoritative resource to define the cilnical relevance of genes and variants for use in medicine and research.

  • Launched: Sept 2013
  • Phase II: Sept 2017


Buliding a Genomic Knowledge Base:

  • Clinical Validity: Is this gene associated with a disease?
  • Pathogenicity: Is this variant causative?
  • Clinical Utility: Is this information actionable?

Shared Genetic and Helath Data by:

  • Patients
  • Clinicians
  • Laboratories
  • Researchers

-> Improve Patient Care Through Genomic Medicine

Clinical Validity

ClinGen developed semi-quantitative framework to classify strength of evidence for the role of genes in disease

Curated by:

  • Genetic Evidence
    • Case-level
    • family segregation
    • case-control data
  • Experimental Evidence
    • Expression
    • model organism
    • rescue studies
    • etc.


Definitive -> Strong -> Moderate -> Limited -> No Evidence Reported -> …


Muti-pronged effort needed for variant curation and interpretation

  • Public sharing of variant interpretations via ClinVar
  • Inter-laboratory conflict resolution
  • Engaging experts in systematic consensus driven interpretation of variants (Expert Panels)
  • Sequence Variants and Copy Number Variants

ACMG standards and guidelines

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommentdation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sequence Variant Interpretation WorkGroup

  • refinethe ACMG/AMP guideline as they are deployed by the community
  • move towards a more quantitative framework

i.e papers:

  • Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion
  • Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework


  • Variant Curation Interface
  • CliGen Allele Registry
    • provides identifiers (CAID)
  • CliGen’s Variant Curation Expert Panels Progress
    • Define WG and plans
    • Develop Variant Classification rules
  • FDA Recognized Genetic Variant Database
  • GlinGen is a GA4GH Driver Project

Clinical Utility

ClinGen developed a framework to provide a transparent and systematic evidence base for prioritizing genes based on their clinical actionability.

Clinical Actionability

  • Well established clinical interventions
  • Specific to the genetic disorder under consideration
  • Lead to disease prevention or delayed onset, lowered clinical burden, or improved clinical outcomes

Classification Matrix

Severity -> Likelihood -> Effectiveness of Intervention -> Nature of Intervention

How engaging patients


  • Patient portal to engage patients in data sharing
    • Collects patient-entrted health information and genetic data extracted from genetic test reports
    • Transfers data into secure ClinGen-hosted environment
    • Connects patients with researchers and with other patients with the same condition


  • Ancestry and Diversity WorkingGroup
  • Engage and Train the Broader Community

Population Data

Applying ACMG/AMP population data criteria for variants with low allele frequency and homozygous/hemizygous occurrences


  • Population data in the context of ACMG/AMP criteria
    • Variants with low allele frequence
    • Considerations regarding zygosity
  • Both pathogenic and benign evidence

Some key point

  • Presence in gnomAD $\ne$ benign
  • Absence in gnomAD $\ne$ pathoegnic
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