Primary review of variants¶

The patient’s “Audit” tab in Congenica shows all Genomics England Tier 1 and 2 SNVs, all Tier A SVs, and all Tier 1 and 2 STRs. See here for further guidance on Genomics England tiered variants.

The patient’s “Variants” tab shows all variants loaded into Congenica - see Viewing All Variants for further info

Review tiered SNVs, CNVs and STRs in the Audit tab¶

After clicking the proband you wish to view, navigate to the “Audit” tab (Figure 7) to view a list of all Tier 1 and Tier 2 SNVs, in the ‘Tiered SNVs without decisions’ table. All Tier A CNVs will be presented in the ‘Tiered SVs without decisions’ table. All Tier 1 and 2 STRs will be presented in the ‘Tiered STRs without decisions’ table.

The variant tier can be viewed in the column next to “Confirmation” (not shown in the following screenshots). This column will also show whether the variant was tiered using the Complete Penetrance (CP) pipeline or the Incomplete Penetrance (IP) pipeline, where relevant (Figure 22).

This example shows variants that have been reviewed and have had decisions made.

To begin variant assessment, click on the variant of interest in the list (Figure 8).

For SNVs, a pop-up of relevant information for the selected variant will open (Figure 9), containing all the information about the variant, ready for review.

For CNVs and STRs, selecting a variant will link users directly to that variant on the Variants tab for further review.

All documented information about the variants can also be found in the [Variants](../additional-features/#viewing-all-variants tab of the proband record (Figure 10).

Users will need to use the Variants tab if they wish to use the ACMG classification feature.

For further details about the ACMG classification feature, please refer to the full Congenica user manual

Viewing visual data in the Congenica Genome Browser¶

To view visual data in the Congenica Genome Browser, select the “Browser” tab (Figure 9) in the variant pop-up and interrogate available information (see the full Congenica User Guide for a description of the available tracks).

For more details about the variant-level information available in Congenica, please refer to the full Congenica user manual

Linking to CVA¶

Genomics England’s CVA can be accessed via the GeL CVA tab, found between the Segregation and Coverage tabs in the detailed variant view. Two links are provided on this tab; Select the appropriate link to navigate to the CVA website and query the data. For more information on CVA and the information it can provide, please see the CVA Portal.

Assigning a decision to a variant¶

The fields in the right-hand column of the Variant Review pop-up (Figure 9) are for recording decisions about a variant. Decisions that can be recorded include: - Pathogenicity - Contribution to Phenotype - Report Category and - Confirmation Status

• For SNVs, the ACMG Guidelines Calculator can be used to aid collation of evidence.

For further information about assigning variant decisions and the ACMG Guidelines Calculator, please refer to the full Congenica user manual

Sending the analysis for Secondary Review¶

After finishing making decisions on a patient’s variants, go to the Audit tab and click the “Submit for 2nd review” button on the “Audit” tab.

The patient status changes to Secondary Review. Another user can now review the decisions made on this patient’s variants, in the Audit tab.

Performing secondary review¶

A second user now can now review the decisions made for each variant on the Audit tab and can approve or reject them (but cannot alter the decision itself).

For example:

Here the pathogenicity itself cannot be changed: the second reviewer can either approve the decision (click the green tick) or reject it (click the red cross).

Approving decisions¶

Once all decisions for all variants on the Audit tab have been approved, the patient Status automatically changes to Final review pending (alternatively, click the green “Approve all pending decisions” button on the “Audit” tab to do this).

Users cannot approve / reject their own decisions¶

The Double-user check workflow enforces independent checking of decisions by a second user.

See "Sample review workflow (patient Status)" in the Congenica User Guide for more about the Double-user check workflow and patient status.

Final review and authorisation of decisions¶

Users with Authoriser permissions can now review the analysis and authorise the final result. The Authoriser could be a third user, not previously involved in the review, or one of the two previously involved.

For further information about result authorisation please refer to the full Congenica User Guide, available via the About link at the foot of the page in Congenica - click this, select your jurisdiction (United Kingdom) then click the Instructions for use link.

Variant confirmation¶

For each variant requiring confirmation change the “Confirmation” status to “Sent for confirmation” in the variant confirmation drop-down (Figure 16). This can be accessed in the variant pop-up in the “Audit” tab.

To export the list of variants into a .csv file for confirmation and/or primer design, close the pop-up and return to the full “Audit” tab. Click “Download .csv” (Figure 17) and select from “Export all” or “Export all to be confirmed” to download information necessary for variant confirmation.

Completing a variant review¶

Once confirmatory analysis has been performed, Confirmed or Failed Confirmation can be recorded in Congenica, using the variant confirmation drop-down (Figure 16).

Once all information is entered, including any additional comments the user wishes to add, complete the analysis and lock down the results by clicking “Review Complete” in the “Audit” tab (Figure 18).

Variant Interpretation Logs¶

Genomics England are currently implementing variant interpretation log (VIL) extraction from Congenica. VILs will contain the information the user has entered during variant interpretation, such as ACMG scores and comments. This data will then be made available in CVA, and will ensure variant interpretations are still accessible after the case has been deleted from Congenica.

VILs will only be extracted for variants that have an approved decision recorded against them, and are visible in the “Decisions made on X” section of the audit tab. Therefore, if you have left comments on a variant, but have decided not to interpret it, please set the Pathogenicity to "Excluded" so that your comments will still be extracted in the VIL (Figure 19).

ACMG scores and criteria can only be extracted for ACMG classifications that have been "locked" using the padlock button (see screenshot). Once locked, the ACMG classification should appear in the Audit tab in Congenica (Figure 20).

VILs will be extracted when a case is marked as 'Review complete' in Congenica. If a case is subsequently re-opened, and further interpretations are made, new VILs will be extracted when the case is next marked as 'Review complete' to ensure we always have the latest data in CVA. Note however, that the previous VILs will not be overwritten, and all versions of the VIL will be available in CVA.

The following data will be captured in VILs:

• Variant coordinates and selected transcript
• ACMG evidences, comments and classification
• Variant comments
• Flagged articles and comments
• Pathogenicity
• Confirmation result

The following data will not be captured in VILs:

• Attached files in the comments section
• Usernames and full audit trail - full audit logs are available on request from service desk. See GUI-EXT-002 Submitting an Audit Request for NGIS User Guide
• Unlocked ACMG scores (see above)
• Variants that don't have an approved "decision"

Generating Summary of Findings in Congenica¶

Summary of Findings are managed by the Genomics England Interpretation Portal. Information about how to access and use the Interpretation Portal is available here.

Currently in Congenica, it is possible to export summary of findings in “structured” (JSON) format. This JSON data can be downloaded directly to NHS computers and is also accessible via the CIP-API system

The JSON data can then be integrated into the GLH’s local LIMS system, or, can be downloaded as a HTML formatted report from the CIP-API (or via the Interpretation Portal).

Details of how to programmatically access the CIP-API can be found here

Details of the JSON data model can be found here.

Exporting JSON report data from Congenica: To generate a Primary Finding report JSON for a patient, navigate to the “Reports” tab and click “Generate new report” (Figure 21).

Select the JSON report template to be used from the drop-down. Optionally, enter a summary of the interpretation in the “Genomic Interpretation” field in the reporting pop-up and click “Save Report” when ready. This creates a JSON file in the format of the Rare Disease Clinical Report Model which can be downloaded and integrated into GLH LIMS, if required.

Any variant that is classified as a ‘Primary Finding’ will be included in this report.

Generating the report will transfer the request ID/case from ‘To be reviewed’ to “Pending Outcomes” in the Genomics England Interpretation Portal. At this point, the Reporting Outcomes Questionnaire must be completed in the Interpretation Portal. The case cannot be closed until this questionnaire has been completed. Once the questionnaire has been completed, the case will move to the ‘Reported Cases’ tab in the Interpretation Portal. See here for further information