ClinVar Notes

This section contains notes regarding ClinVar and its integration into VarFish. It outlines issues with the interpretation of variants as well as their resolution in VarFish and the rationale for the taken decisions.

ClinVar entries have two major labels:

variant assertion

The assertion about the pathogenicity of a variant, e.g., likely benign or pathogenic.

review status

A grading of how well a variant is reviewed. This is shown as a star rating on the ClinVar website.

Some reference ClinVar records (RVC identifiers) refer to one submission (SCV identifiers). Multiple reference ClinVar records are summarised in variant ClinVar records (VCV identifiers).

Review Status Interpretation

The interpretation of the status of a ClinVar record can be challenging. This is caused by two points.

Overall, there are the following occurences in ClinVar of clinvar assertion (June 4, 2020). Note that some only make sense together with the others (e.g., “no conflicts” only makes sense if there is more than one submission).

Count	ClinVar Status
12,342	conflicting interpretations
839,966	criteria provided
55,467	multiple submitters
71,858	no assertion criteria provided
17,068	no assertion provided
55,467	no conflicts
5,751	practice guideline
11,172	reviewed by expert panel
772,157	single submitter

In ClinVar the star ratings are assigned as follows

Stars	Description
none	no assertion criteria provided OR single submitter, no assertion provided
one	single submitter, criteria provided OR criteria provided & multiple submitters, conflicting interpretations
two	criteria provided, multiple submitters, no conflicts
three	reviewed by expert panel
four	practice guideline

In particular, the missing distinction between “no assertion criteria provided” and “no assertion provided” is misleading. Also, it can be misleading that records with an assertion criteria override those without. In several records, good literature has been curated without an assertion criteria while many records from clinical testing companies have an assertion criteria but no phenotype and less diligence has been made as with good research.

Merging of ClinVar Records

The algorithm for merging multiple records in ClinVar to display the VCV records is not public. Also, given the issues with ClinVar’s star rating from above, VarFish uses a modified display from ClinVar’s. Instead of ClinVar’s gold stars, VarFish assigns points.

Points	Condition
none	origin is somatic OR no assertion provided
one	single submitter OR multiple submitters, conflicting interpretations
two	multiple submitters, no conflicting interpretation
three	reviewed by expert panel OR practice guideline

Importantly, Varfish will still display all ClinVar records in the variant display and link out to ClinVar so the user can make their own assessment. The role of ClinVar in VarFish is to assist the user in quickly find variants present in ClinVar and not to override the user in any way.

The rationale:

• ClinVar entries for somatic variants and those without a variant assessment are of little interest.

• Multiple submitters are better than one submitter, regardless of the assertion criteria. Requiring assertion criteria or expert panel status is good for ClinVar to foster submission of assertion criteria or applications for expert panels but less important for VarFish users.

• Variants for practice guideline are less important for VarFish’s use case. Thus, collapsing them with “reviewed by expert panel” should not make a problem.

VarFish merges ClinVar records based on the following algorithm.

0. Generally, benign and likely benign is merged to likely benign/benign, same for pathogenic and likely pathogenic. Records with uncertain significance are ignored in merging if there is at least one (likely) benign/pathogenic assessment.

1. Records flagged with practice guideline or expert panel will be assigned three points and override any other assessment. Within three point variants, practice guideline beat expert panel.

2. In the case that there is only one record, that record’s assessment is used. Note that this will include RCV records in ClinVar that are already merged. Assign one point.

3. In the case of two or more records:

   • Ignore uncertain significance records as outlined in (0).

   • If there are conflicting interpretations, mark the record as such.

   • Otherwise, merge likely and non-likely assertions and add no conflicting interpretation if more than one non-uncertain significance record.

   • Assign one point in case of conflicts and two points in case of consistency.

Further, each variant is annotated with an ACMG-style rating. In the case of having an “likely X/X” assertion, ACMG:1.5 or ACMG:4.5 is assigned. In the case of conflicting assertions, an ACMG score of 3 is assigned but the variant is flagged with a “C” to indicate conflicting interpretations. Note that uncertain vs. benign does not create a conflict as well as uncertain vs. pathogenic.

Examples

1. INPUT

   • practice guideline, likely pathogenic

   • reviewed by expert panel, likely pathogenic

   • single submitter, pathogenic

   OUTPUT

   • reviewed by expert panel, likely pathogenic

   • three points; ACMG:4-LP

2. INPUT

   • single submitter, pathogenic

   • multiple submitters, no conflict, likely pathogenic

   OUTPUT

   • multiple submitters, no conflict, likely pathogenic/pathogenic

   • two points; ACMG:4.5-LP-P

3. INPUT

   • single submitter, pathogenic

   • single submitter, uncertain significance

   • single submitter, likely pathogenic

   OUTPUT

   • multiple submitters, no conflict, likely pathogenic/pathogenic

   • two points; ACMG:4.5-LP-P

4. INPUT

   • single submitter, pathogenic

   • multiple submitters, uncertain significance

   OUTPUT

   • single submitter, likely pathogenic

   • one point; ACMG:4-LP

5. INPUT

   • single submitter, pathogenic

   • multiple single submitters, likely benign

   OUTPUT

   • multiple submitters, conflicting interpretations, uncertain significance

   • one point; ACMG:3