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
Ecosystem
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.
Classification:
Definitive -> Strong -> Moderate -> Limited -> No Evidence Reported -> …
Pathogenicity
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
Others
- 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
GenomeConnect
- 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
Others
- Ancestry and Diversity WorkingGroup
- Engage and Train the Broader Community
Population Data
Overview
- 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