ClinVar

Guidelines for Applying for Review Status in ClinVar

Approved by the ClinGen Steering Committee, January 30, 2015

The ClinVar database is hosted by NCBI and currently focuses on sharing variant-centric information. As part of the submission process, the entity submitting information is asked to provide an assertion with regard to “Clinical Significance”.

In order for users of ClinVar to have additional information with regard to the level of review of the submissions, ClinVar has developed a four star rating system, representing the “Review Status” of each submission.  By default, ClinVar submissions have the review status "single submitter - criteria not provided".  However, submissions may obtain the statuses of "single submitter - criteria provided", "expert panel" and "practice guidelines" according to the descriptions below. Full implementation is scheduled for June 2015.

Single submitter - criteria provided – one star

The one star review status refers to “single submitter - criteria provided” assertions. For a submission to achieve this status, the submitter must:

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)
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.
3. Provide a publication or other electronic document (such as a 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 (link provided for all submitted assertions).
4. Submit available supporting evidence or rationale for classification ( e.g. literature citations, total number of case observations, descriptive summary of evidence, web link to site with additional data, etc .) or be willing to be contacted by ClinVar users to provide supporting evidence. In other words, 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 will provided on our submission forms. Note that if a submission includes multiple records, designations for each can differ, namely either 'single submitter - criteria provided' or  'single submitter - no criteria provided'.

Expert panel – three stars

The three star review status refers to “expert panel” assertions.  Groups seeking expert panel designation should submit the information described below using this form:

ClinVar Expert Panel request form (maximum of 3 pages)

and send to clinvar@ncbi.nlm.nih.gov .

The information provided on the expert panel request form will be posted on the ClinVar website to provide users information about the groups obtaining this status.

For submitted variants to be assigned Expert Panel criteria level, the submitter must meet all requirements for "Single submitter, criteria provided" as well as the additional requirements described below. Applications for Expert Panel status must be reviewed and approved by the Clinical Genome Resource (ClinGen) program .

Panel Membership

• A membership list must be provided for review when requesting Expert Panel status for submissions.
• 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 represent multiple institutions.
• It is expected that the individuals comprising the expert panel should be international in scope, and are considered by the community to be experts in the field based on publications and long-standing scope of work.
• ClinGen hopes that there is only one expert panel per gene and that the panel is inclusive of known experts in the field. Therefore, if you have expertise in a gene that is already evaluated by an expert panel, please consider joining efforts with the existing panel or provide justification for the necessity of an additional panel.
• We encourage newly forming expert panels to contact ClinGen ( clingen@clinicalgenome.org ) early in the process to discuss the formation of the panel.

Conflict of Interest

Information should be provided with regard to any potential financial conflicts of interest of the panel members and how conflicts are managed.

Practice guideline - four stars

The four star review status refers to “practice guideline” assertions.  Groups seeking practice guideline designation should submit the information described below using this form:

ClinVar Practice Guideline request form (maximum of 3 pages)

and send to clinvar@ncbi.nlm.nih.gov . This information will be reviewed by the ClinGen Steering Committee to make the determination of practice guideline status for clinical assertions in ClinVar.

The information provided on the practice guideline request form will be posted on the ClinVar website to provide users information about the groups obtaining this status.

Please make note of the following points:

1. The submitter must meet all requirements for single submitter - criteria provided and expert panel designation as well as the additional requirements described below.
2. A description of the rating system for strength of evidence utilized, unless already included in the variant assessment method.
3. A description of the external review process for determining the clinical relevance of variants prior to publication
4. A description of how variant interpretations are kept up-to-date