ClinVar

Assertion criteria and review status

To help users assess the quality and consistency of interpretations of each variant's effect, ClinVar computes a value for review status, which is represented graphically by a number of gold stars. In June 2015, this computation was refined to give additional weight to submissions that include the criteria by which the assertion of clinical significance was reached, or the "assertion criteria". In other words, each record submitted is categorized as one of the following:

• no assertion criteria provided (0 stars)
• criteria provided, single submitter (1 star)
• reviewed by expert panel (3 stars)
• practice guideline (4 stars)

and records in the no assertion criteria provided do not contribute to the calculation of gold stars (more...).

Note that assertion criteria does not refer to the experimental method used to call the variant, but the method used to classify the significance of the variant.

Representative documentation of assertion criteria

These examples are provided to help submitters understand what is meant by documentation of "assertion criteria" and guide you in creating your own documentation for your particular assertion criteria. These documents are not intended to be submitted to ClinVar by other groups; please do not include either of these documents in your submission (unless your group provided the sample documentation).

Definitions

No Assertion Criteria Provided

If a submitter does not document the criteria by which an assertion was assessed, then that submission is marked 'no assertion criteria provided'.

Criteria Provided, Single Submitter

For a submission to achieve this status, the submitter must meet all four requirements below:

1. Document that the allele or genotype was classified according to a comprehensive review of evidence consistent with, or more thorough than, current practice guidelines (e.g. review of case data, genetic data and functional evidence from the literature and analysis of population frequency and computational predictions). Note that computational prediction is a part of comprehensive review but is not sufficient. When you provide documentation of your assertion criteria (see point 3), you are attesting that your interpretation was made based on this type of comprehensive review.
2. Include a clinical significance assertion using a variant scoring system with a minimum of three levels for monogenic disease variants (pathogenic, uncertain significance, benign) or appropriate terms for other types of variation. This requirement is achieved by including a value for clinical significance for each interpreted variant in your ClinVar submission.
3. Provide a publication or other electronic document (such as a Word document or PDF) that describes the variant assessment terms used (e.g. pathogenic, uncertain significance, benign or appropriate terms for other types of variation) and the criteria required to assign a variant to each category. This document will be available to ClinVar users via the ClinVar website (a link is provided for all submitted assertions). More than one document per submitting group may be provided, e.g. if you have specific documentation for autosomal dominant vs autosomal recessive disorders, or as your criteria change over time. This requirement is achieved by providing the assertion criteria document(s) to ClinVar and by indicating which document was used as the assertion criteria for each variant interpretation in your submission.
   • If you are sending your submission by email, please include your assertion criteria document(s) as an attachment. In the spreadsheet, please fill out the "Assertion method" and "Assertion method citation" columns for each interpretation to indicate which set of criteria were used for each interpretation.
   • If you send your submission with the Variation Submission Portal, you may upload your assertion criteria when you register your organization or when you send your ClinVar submission. If you upload a submission file, please fill out the "Assertion method" and "Assertion method citation" columns for each interpretation to indicate which set of criteria were used for each interpretation. If you use the ClinVar Submission Wizard, you will be prompted to provide your assertion criteria.
4. Submit available supporting evidence or rationale for classification or be willing to be contacted by ClinVar users to provide supporting evidence. This requirement is achieved by including your supporting evidence in your ClinVar submission (e.g. literature citations, total number of case observations, descriptive summary of evidence, web link to site with additional data, etc.); alternatively, contact information for one person on the submission must be submitted as "public".

ClinVar will not review the details of the variant scoring criteria accompanying a submission. Instructions for completing a submission to meet these requirements are provided on our submission forms. A submission with Assertion method and Assertion method citation provided will be interpreted as an attestation that the content conforms with these requirements. Note that if a submission includes multiple interpretations, designations for each can differ, namely either 'criteria provided, single submitter' or  'no assertion criteria provided'.

Note that submission of assertion criteria is optional, and ClinVar welcomes your submission even if it does not meet all four requirements above.

Reviewed by Expert Panel

For a submission to be assigned the 'reviewed by expert panel' status, the submitter must meet all requirements for  'criteria provided, single submitter' status as well as the additional requirements described here and below. Applications for expert panel status must be reviewed and approved by the Clinical Genome Resource (ClinGen) program.  Designation as an expert panel is attributed to the submitter, and thus applies to all submissions received.

1. Panel Membership - It is recommended that the expert panel include medical professionals caring for patients relevant to the disease gene in question, medical geneticists, clinical laboratory diagnosticians and/or molecular pathologists who report such findings and appropriate researchers relevant to the disease, gene, functional assays and statistical analyses. It is expected that the individuals comprising the expert panel process should represent more than one academic or commercial institution. A membership list must be provided for review when requesting expert panel status for submissions.
2. Conflict of Interest - Information should be provided with regard to any potential conflicts of interest of the panel members and how conflicts are managed.

Practice Guideline

For a submission to be assigned 'practice guideline' status, the submitter must meet all requirements for 'criteria provided, single submitter' and 'reviewed by expert panel' designation as well as the additional requirements described here and below. Applications for practice guideline status must be reviewed and approved by ClinGen.

1. A description of the rating system for strength of evidence utilized, unless already included in the variant assessment method.
2. A description of the external review process for determining the clinical relevance of variants prior to publication
3. A description of how variant interpretations are kept up-to-date

To request approval for expert panel  or practice guideline type, submitters must complete the required form, provided here and submit the form to clinvar@ncbi.nlm.nih.gov for review by ClinGen. The method document will be posted on the ClinVar website to provide users with transparency in variant classification criteria.