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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:

1. 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
2. Perform a literature search to identify relevant publications to support a variant curation
3. Score collected/collated evidence in the ClinGen VCI to determine a provisional classification for a variant-disease pair based on guidelines
4. Present evidence summary supporting provisional classification for expert approval
5. 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

Continuing Medical Education (CME AMA & CME Other)

Accreditation
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of The American College of Medical Genetics and ClinGen - Clinical Genome Resource Genomics and is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation (6 hours per curation – Limited to 17 curations annually)

The American College of Medical Genetics and Genomics designates this enduring material for a maximum of 102 hours in AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NSGC Category 2 CEUs/Genetic Counselors (self-report)

This activity meets requirements to apply for Category 2 CEUs from the National Society of Genetic Counselors (NSGC). Please complete the module and submit your certificate to NSGC, using the instructions for “How To Submit a Category 2 CEU Application in the NSGC CEU Portal.” ACMG is the accredited sponsor. You must apply within three months of the activity date, but you will be able to submit up to 17 curations under one fee for this activity. 

Learner Data Consent

ACMG Education reports learner data to respective agency boards and you will be asked for consent during the evaluation process. Your compliance with deadlines and completing evaluations are part of the process in meeting learner needs and ACMG’s education mission.

Claiming your Educational Credits

• Invitation code
• 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 (required for self-reporting)

Please note: 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.

Accredited Continuing Education Financial Disclosure

The American College of Medical Genetics and Genomics (ACMG) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide Accredited Continuing Education (ACE) for physicians. ACMG is an organization committed to improvement of patient care and general health by the incorporation of genetics and genomics into clinical practice.

ACMG has implemented the following procedures to ensure the independence of ACE activities from commercial influence/promotional bias, the Accreditation Council for Continuing Medical Education (ACCME) requires that providers (ACMG) must be able to demonstrate that: 1) everyone in a position to control the content of an ACE activity has disclosed all financial relationships that they have had in the past 24 months with ineligible* companies; 2) ACMG has implemented a mechanism to mitigate relevant financial relationships; and 3) all relevant financial relationships with ineligible companies are disclosed to the learners before the beginning of the educational activity. The learners must also be informed if no relevant financial relationships exist.
*Ineligible companies are defined as those whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

ACMG Education Policies

Please review the policies below regarding the ACMG Education program

• Financial Disclosures and Mitigation Procedure
• ACMG Content Validation Policy
• ACMG Content Branding Policy

All of the relevant financial relationships listed for these individuals have been mitigated.

Disclaimer

ACMG educational programs are designed primarily as an educational tool for health care providers who wish to increase their understanding of the application of genomic technologies to patient care. The ACMG does not endorse or recommend the use of this educational program to make patient diagnoses, particular by individuals not trained in medical genetics. Adherence to the information provided in these programs does not necessarily ensure a successful diagnostic outcome. The program should not be considered inclusive of all proper procedures and or exclusive of other procedures and that are reasonably directed at obtaining the same results. In determining the propriety of any specific procedure or, a healthcare provider should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.

Questions regarding CE credit should be directed to education@acmg.net