Variant Pathogenicity Training Materials

Interested in Variant Curation? The following documents and presentations are available to help people learn and understand the variant curation process, as well as ClinGen's efforts to modify ACMG variant assessment criteria. In order to get involved with our Variant Curation activities, please review the information on our ClinGen Community Curation Working Group page and fill out our volunteer survey. Please note that Variant Curation is a comprehensive volunteer activity and on average, 8-10 hours of effort is required each month. For questions about existing materials or requests for new materials, contact us at [email protected].

Required

Variant Curation Standard Operating Procedure, Version 3

Detailed documentation outlining the variant curation process.

Start Variant Curation Standard Operating Procedure, Version 3
Required

2015 ACMG/AMP Sequence Variant Interpretation Guidelines

The guidelines are freely available through PubMed Commons.

Start 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.
Required

SVI General Recommendations for Using ACMG/AMP Criteria

SVI provides general recommendations for using the ACMG/AMP criteria to improve consistency in usage and transparency in classification rationale.

Start Sequence Variant Interpretation
Required

Video Tutorials

Videos describing how to use the ClinGen Allele Registry, as well as an overview of searching the literature for sequence variant evidence, including tips and tricks on effective use of variant nomenclature in your search, where to look and common literature search speed bumps, and how to overcome them.

Start Using the ClinGen Allele Registry
Start Sequence Variant Literature Search Tips and Tricks
Required

Live VCI Training

Attend a live Variant Curation Interface (VCI) training to learn more about how to enter information for variant curations. The ClinGen Community Curation Group will contact you regarding this training, once you have either emailed [email protected] or filled out the volunteer survey below. (Please use this option if you would like to volunteer to curate with ClinGen).

Start ClinGen Community Curation (C3)
Start ClinGen Volunteer Survey
Required

Attestation & Group Assignment

Once you have read through all of the information and attended a live VCI training session, you will be sent an attestation form to fill out. Once your attestation form is complete, the ClinGen Community Curation Group will contact you with your group assignment.

Required

VCEP-specific ClinGen Variant Curation Training, Level 2

Level 2 variant curation training aims to educate the biocurator on the specific ACMG/AMP guideline specifications and variant assessment procedures outlined by their assigned variant curation expert panel (VCEP).

Start ClinGen Variant Curation Training, Level 2 (VCEP-specific)
Optional

OPTIONAL Items

These OPTIONAL items include a video tutorial by Dr. Steven Harrison on "Variant Interpretation and the ClinGen Curation Interface Tool," the Standardized Text for ClinGen VCEPs, and the Variant Curation Interface Help Document.

Start Interpreting Genomes: Variant Curation Video
Start Standardized Text for ClinGen Variant Curation Expert Panels
Start Variant Curation Interface Help Document
Start ClinGen Variant Curation Expert Panel Procedures and Resources

ViewClinGen Guidance to VCEPs regarding the use of gnomAD v4

Supporting Documents - August 7, 2024

ViewClinGen SVI PVS1 Decision Tree Editable

Supporting Documents - July 12, 2024

ViewClinGen SVI Splicing Subgroup - Response to Feedback

Supporting Documents - March 22, 2024

ViewClinGen VCEP Recuration Standard Operating Procedure

Supporting Documents - July 28, 2023 - ClinGen's recommendations for re-evaluating previously approved variant pathogenicity classifications.

ViewVariant Curation Standard Operating Procedure

Training Materials - October 21, 2022

ViewVariant Curation Standard Operating Procedure, Version 3

Curation Activity Procedures - October 21, 2022

ViewClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Curation Activity Procedures - August 19, 2022 - Release notes from v1.0 to v1.1 The following criteria descriptions wer emodified for clarity based on feedback: PS2 modified to make the distinction between PS2_strong vs PS2_moderate more clear and provide an example within the text; PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section; PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or.49; BA1 and BS1 calculations corrected, rational provided in supplement; BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion; BP2 modified to indicate that this criterion can be used for either a cis or trans variant; BP4 modified to be consistent with detailed description provided later in the document Archived Document

ViewClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.2

Curation Activity Procedures - August 4, 2022 - Release Notes from v1.1 to v1.2: Typo corrected, “Variants generating PTCs 5’ of c.1714 of NM_000545.8..." corrected to "Variants generating PTCs 3’ of c.1714 of NM_000545.8...” Archived Document

ViewClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines

Curation Activity Procedures - March 29, 2022 - ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A (Version 2) and for OTOF and MYO15A (Version 1) Archived Document

ViewClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

Curation Activity Procedures - March 29, 2022 - Summary of changes from Version 3: (1) Specification of PM5_Supporting to nonsense and frameshift variants that are predicted/proved to undergo nonsense-mediated decay (NMD) or located upstream of the last known pathogenic truncating variant [c.2506G>T (p.Glu836Ter)], (2) Column correction for PM2_Supporting from Moderate column to Supporting column. Archived Document

ViewClinGen Malignant Hyperthermia Susceptibility Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2

Curation Activity Procedures - March 1, 2022 - Changes from v1: Revised PS4 such that at all strength levels an individual with two VUS/LP/P variants in RYR1 cannot be considered as supporting pathogenicity of either variant., PS1 can be used at level moderate for previously classified likely pathogenic variant at the same codon with the same amino acid change., PM5 can be used at level supporting for previously classified likely pathogenic variant at the same codon, different amino acid change., PM1 should be downgraded to supporting when either PS1 or PM5 are used. Archived Document

ViewClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.1

Curation Activity Procedures - February 25, 2022 - Changes from v1: Corrected combining rules for LP to include PVS1 + PM2_Supporting = LP Archived Document

ViewClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Curation Activity Procedures - December 13, 2021 - Summary of changes in Version 2: Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools. Archived Document

ViewClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.2

Expert Panel Applications - November 9, 2021 - Release Notes/Changes from v1.1: Updated for clarification on PM3 and BP2, and typo correction. Archived Document

ViewClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

Curation Activity Procedures - November 1, 2021 - Release Notes/Changes from v2: Updated MONDO ID for Glanzmann thrombasthenia from MONDO: 0010119 to MONDO: 0100326 Archived Document

ViewClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Curation Activity Procedures - September 30, 2021 - Release Notes/Changes from v1: Typo corrected, “p.Leu197_Leu205del” in v1 replaced with “p.Lys197_Lys205” in v1.1 Archived Document

ViewClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3

Curation Activity Procedures - September 20, 2021 Archived Document

ViewClinGen Variant Curation Training, Level 1

Training Materials - September 1, 2021 - Level 1 variant curation training aims to familiarize variant biocurators with general variant assessment information and ClinGen procedures/resources.

ViewClinGen Variant Curation Training, Level 2 (VCEP-specific)

Training Materials - September 1, 2021 - Level 2 variant curation training aims to educate the biocurator on the specific ACMG/AMP guideline specifications and variant assessment procedures outlined by their assigned variant curation expert panel (VCEP).

ViewClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Expert Panel Applications - April 16, 2021 - Release Notes/Changes from v1: Corrected formatting and typos (April 2021) Archived Document

ViewVariant Curation Standard Operating Procedure, Version 2

Curation Activity Procedures - January 29, 2021 Archived Document

ViewSVI Functional Assay Documentation Worksheet

Supporting Documents - May 8, 2020

ViewClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Curation Activity Procedures - September 10, 2019 Archived Document

ViewVariant Curation Standard Operating Procedure, Version 1

Training Materials - April 26, 2019 Archived Document

ViewClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Curation Activity Procedures - September 19, 2018 Archived Document

ViewBA1 Exception List

Supporting Documents - July 30, 2018

ViewPS2/PM6: Recommendation for de novo PS2 and PM6 ACMG/AMP criteria (Version 1.1)

Supporting Documents - March 18, 2018 - Updated May 2021, changes from v1: Clarified that confirmed/assumed is with regards to parental relationships and not de novo status

ViewStandards 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.

Supporting Documents - May 17, 2017 - The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.