ClinGen Variant Pathogenicity Curation Module
Date of Release: January 4, 2023
Expiration Date: December 31, 2024
Credits offered: 102 CME, , NSGC Category 2 (Self-report)
Estimated time for completion: Up to 6 hours per curation (limit of up to 17 curations) Please note: It is recommended that variant curations be submitted in batches of at least 2.
Course must be completed by the expiration date
Overview
The Clinical Genome Resource (ClinGen, https://www.clinicalgenome.org/) is an NIH-funded resource dedicated to building an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. ClinGen’s variant pathogenicity curation activities utilize the “Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology” (Richards et al. 2015, PMCID: PMC4544753) which provides an evidence-based framework to classify sequence variants associated with Mendelian disorders into a five-tier nomenclature system. These guidelines describe the process for classifying variants into five categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign) based on criteria using evidence such as population data, computational and predictive analysis, functional criteria, and allelic and co-segregation data.
ClinGen Variant Curation Expert Panels (VCEPs) develop disease-gene specifications to the Richards et al.
ACMG/AMP guidelines for gene-disease pairs within a particular clinical domain. VCEPs consist of members with clinical care, research, and diagnostic laboratory expertise within that domain, as well as biocurators with experience in the variant pathogenicity curation process. Members use their ACMG/AMP specifications and publish the classifications in ClinGen’s Evidence Repository and NCBI’s ClinVar database, both of which are publicly available. In addition, ClinGen’s VCEP assertions in ClinVar are recognized by the FDA as part of their “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics.” In most cases, a biocurator completes a variant assessment and arrives at a provisional classification, followed by presentation of the data to the VCEP for expert review and final approval. VCEPs utilize the ClinGen Variant Curation Interface (VCI) for documentation of variant pathogenicity classifications.
Learning Objectives:
At the conclusion of this session, participants should be able to:
- Use the ClinGen vetted variant pathogenicity curation process to evaluate the strength of evidence supporting or refuting a variant-disease relationship and to classify variants based on ACMG/AMP guidelines
- Perform a literature search to identify relevant publications to support a variant curation
- Score collected/collated evidence in the ClinGen VCI to determine a provisional classification for a variant-disease pair based on guidelines
- Present evidence summary supporting provisional classification for expert approval
- Confirm VCEP approval of variant classification, which will then be published to the ClinGen Evidence Repository (https://erepo.clinicalgenome.org/) and submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/)
For the purpose of this module, learning objectives will be demonstrated by the learner submitting documentation of a ClinGen VCEP-approved variant-disease curation final evidence summary from the ClinGen Evidence Repository https://erepo.clinicalgenome.org/. Per ClinGen VCEP policies, this variant curation will also be submitted to ClinVar.
Target Audience:
This ClinGen Variant Pathogenicity Curation module is intended to provide learners with educational credit for participating in ClinGen variant curation activities and is available to individuals who are existing members of Step 4 approved ClinGen VCEPs and have had at least one variant curation previously approved by a ClinGen VCEP.
Course Requirements
- Invitation code
- Must be a curator of an approved (Step 4) ClinGen VCEP
- Variant must have at least 1 publication
- Provide a record of a ClinGen VCEP-approved, published classification below, including:
- Variant ID (ClinGen Allele Registry ID or ClinVar Variation ID)
- Approval date (must be within same calendar year)
- eRepo URL
- PMIDs (to verify minimum 1 publication requirement)
- Evaluation and self-report in the ACMG Genetics Academy Click here (required for educational credits)
- In the Self-report section, you will be asked how many CMEs are requested. 1 CME is the equivalent of one hour. Please use that field to document the number of hours (maximum of 6) you spent gathering, evaluating and scoring evidence as well as presenting to the VCEP for approval.
References
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30