Summary

The Clinical Variant Ark (CVA) Portal is now in BETA! This means it is available to assist you in the interpretation of your 100K Genome cases. Going forward, we will gather feedback to improve the user experience and introduce new features to help you with your cases.

As a beta, some features may not work as expected yet and we have outlined these in the sections Using CVA and Known issues. We will be keeping you updated about improvements we make to CVA in future release notes, but if you spot anything amiss or would like to see a feature added, contact the Genomics England Service Desk .

What is CVA?

CVA is the knowledge base component of the Interpretation Platform. The knowledge is built from the cases and their interpretations in the 100K Genomes Project and in the future, the NHS Genomic Medicine Service.

Every time a case is processed through the Interpretation Platform the HPO terms, Pedigree, Gene Panel etc. associated with that case are deposited into CVA. Alongside this phenotypic data we also store the results of Interpretation Services that may have been applied to the case during its processing through the platform e.g. results of tiering.

Additionally, when a case is reviewed or interpreted by a user of the Interpretation Platform, for example, by a Clinical Scientist in a GMC using a Decision Support System, the results of that Interpretation are stored in CVA. In this way CVA could be thought of as a database of needles pulled out of genomic haystacks! CVA is therefore constantly being updated with high quality genotype to phenotype links and evidence which is hugely valuable information.

Access:

• CVA Portal BETA can be accessed on the HSCN network here: cva.genomicsengland.nhs.uk
• Support for Research and Public users will be available as part of phase 2

Main features:

• CVA is a knowledge base built from the 100K Project and in the future the Genomic Medicine Service
• It stores clinically relevant variants and their associations to phenotypes with fine grained detail, for all stages of interpretation, in each specific case where a variant was observed

You can:

• Explore high-quality clinically relevant association between genotypes and phenotypes
• Determine similarities between rare disease cases based on the Human Phenotype Ontology term
• Find rare disease cases and variants through various ways, including panels, phenotypes in genes** **

CVA in numbers:

At the time of writing, there are:

• 2,132,835 variants
• 21,938 rare disease cases:
  • 917 cases with a positive primary finding, 5,218 with a negative primary finding
  • 15% overall diagnosis yield
  • 29 inconclusive cases

Using CVA:

This list includes features you may need to consider when using the beta CVA Portal:

• CVA displays rare disease cases for now - we hope to add support for Cancer cases during 2019.
• Phenotypes are represented using HPO terms and HPO IDs
• Gene symbols are represented using HGNC
• Consequence types are represented using Sequence Ontology
• CVA is designed primarily for desktop applications
• CVA currently has two main views, one for Cases and one for Variants. A Gene View is planned for 2019
• Variants are represented in GRCh38 unless indicated otherwise. When viewing a GRCh37 case, you will see variants displayed as GRCh37. If you decide to view a variant of that case, then you will see the GRCh38 variant location unless there is no GRCh38 equivalent.

Search:

• Searching by a HGNC gene symbol will only look for genes that are included in a case's Summary of Findings or Reporting Outcomes Questionnaire
• Search will return variants as represented in GRCh38 unless otherwise stated by adding 'GRCh37' to the search term. E.g. GRCh37 4:14564353:A>C
• Searching for either a Clinical Indication e.g. "Brugada Syndrome", a Gene Panel e.g. "LQT Syndrome" or a HPO term e.g. "Prolonged QTc interval" or HP:0005184, will return all cases that have had one of those search terms associated with the case

Filters:

• Filters with multiple options operate with an 'OR' logic. E.g. Filter variants by 'Tier 1' or 'Tier 2'
• Multiple filters use an 'AND' logic. For example, filter variants that are 'Tier 1' or 'Tier 2' and located in gene 'NARS2' or 'AAAS'
• Gene filters currently only work with HGNC gene symbols
• Phenotype filters currently only work with HPO terms

Cases:

• All variants displayed in a case are represented by the case's assembly version
  • You can view variants in an alternative assembly version if it exists within CVA
  • Case Statuses:
    • To Be Reviewed: The case has yet to be interpreted by the end user
    • To Be Closed: A Summary of Findings has been generated for the case but the Reporting Outcomes Questionnaire is still to be completed
    • Archived: A Reporting Outcomes Questionnaire has been completed for the case.
• Cases in the "To Be Closed" and "Archived" status can have an additional "Primary Findings" status which, for Rare Disease cases is relevant to the ACMG classification of variants in a case:
  • Positive Primary Findings:
    • At least one variant included in the Reporting Outcomes Questionnaire is 'pathogenic' or 'likely pathogenic'.
  • Negative Primary Findings: either: A) all variants in the Reporting Outcomes Questionnaire are 'benign' or 'likely benign' B) at least one variant is a 'variant of unknown significance' and the other variants are 'benign' or 'likely benign' C) No variants are included in the Reporting Outcomes Questionnaire
  • Inconclusive Primary Findings:
    • all variants in the Reporting Outcomes Questionnaire are 'variants of unknown significance'

Providing Feedback

We have been developing the CVA Portal with input on requirements from a number of different users from GMCs and GeCIPs, if you would like to be involved please contact the Genomics England Service Desk

Known issues:

These are issues that we are aware of and will be working to resolve:

Search issues:

• Search results do not always display exact results matching at the top
  • This can be mitigated by using the browsers in-page search tool when the search results have been loaded (Keyboard shortcut: Ctrl+F on PC, CMD+F on Mac)
  • Searching with numeric characters return results displaying the copy 'Match found within panels, phenotypes or genes'. This is incorrect
  • Its currently not possible to filter variant search results e.g. by pathogenicity, this is on our to do list

Filter issues:

• When using filters that require typing such as a genes or phenotype filter, it may take longer than expected for suggestions to appear

Case issues:

• The links to show the Summary of Findings and Reported Outcomes Questionnaires from the Case View page are currently broken, we are working to fix this ASAP
• Some cases may not display any variants, please report these to the service desk
• If you search for a HPO term, you may find that the HPO terms displayed in the case is represented differently
• HPO terms may be represented as HPO ID when viewing a case -- this happens when the connection to the EBI server is interrupted.
• Clinical Indications may be duplicated multiple times in a case
• There is currently no support for cancer cases in the CVA Portal, this is planned for 2019.