VCI Curation Help

Variant Curation Interface Help Doc

REGISTRATION

1. When to Register

You can explore the ClinGen test/demo curation interfaces (https://curation-test.clinicalgenome.org/) without registering as a ClinGen curator (see ‘Demo Login’ instructions below); however we encourage those who want to explore the interface more thoroughly to register their email with us (see section below for information on how to register). We recommend curators become familiar with the interface by exploring the test interface before curating “real” evidence into the production interface.

ClinGen curators who would like to access the production version of the ClinGen curation interfaces (https://curation.clinicalgenome.org/) will need to register for production interface (see section 2, below, on how to register). Data entered into the production interface is permanently saved, so this interface should only be used for “real” curation.

2. How to Register

i. If you are a ClinGen curator, you may request an account by emailing us at [email protected]. The ClinGen Variant Curation Interface is available for public use. The ClinGen Gene Curation Interface is restricted to use by ClinGen curators. If you would like to collaborate on gene curation, please contact ClinGen at [email protected].

ii. When you write to us please let us know the following:

a. Your preferred email address (which you will use to log in to the interfaces)

b. Your preferred display name (first and last name)

c. Any affiliation you have with ClinGen

iii. We will write back to you to confirm that your email address has been registered and can be used for logging in to the interfaces.

LOGGING IN

1. 2.0 Login Transfer

In December 2020 a rearchitected VCI/GCI platform was launched. If you had a login before December 2020 your account has been transferred along side all of your curation data and affiliations. To access your curations within the new platform please see here.

2. Demo Login

You can try out the test version of the ClinGen interfaces (https://curation-test.clinicalgenome.org/) by simply clicking on the 'Demo Login' button in the header. You will be logged in to the test version of the interfaces under a generic “ClinGen Curator” account.

images coming soon.....

3. ClinGen Registered User Login

In both the test/demo (https://curation-test.clinicalgenome.org/) and production (https://curation.clinicalgenome.org/) versions of the ClinGen curation interfaces users who have registered an email address with us can login by clicking the “Login” button in the header.

a. If you are a first time user you will need to go to the “Sign Up” tab and enter your registered email address, enter your desired password, and then click “Sign Up.”

As a first time user, you will also need to be verified by Auth0. When you sign up you will be sent an email in which you need to click the link in order to verify your account. After doing this you should be able to now “log in” using your email and password.

b. If you are a returning user accessing the interfaces from a different operating system then you will see the pop-up above, in which case you should re-enter your registered email address and your selected password on the “Log In” tab and then click “LOG IN.”

c. If you are a returning user accessing the interfaces from your usual operating system then your last log in details will likely be saved and you will see the pop-up shown below, in which case you only need to click on your email address to login.

4. Login Troubleshooting

i. Have you registered your email address by emailing us at [email protected]? ii. Have you received confirmation from us that your email address has been registered?

AFFILIATIONS

1. What is an Affiliation?

An Affiliation is any set of people collectively represented in ClinGen resources (e.g. ClinGen Working Groups, ClinGen Expert Panels, Research Labs, Clinical Labs, etc.) that collectively:

Edit and score/evaluate evidence
Work on the same classification/interpretation
Approve the same classification/interpretation

2. Select and Change Affiliation

If a user is as a member of at least one Affiliation, then after logging in they can select an affiliation they are a member of to curate in, in which case all actions they take will be attributed to the selected Affiliation. The affiliation one is currently logged in as is always noted in the top bar of the VCI (A) this is also where you can change affiliations. Clicking on "Change Affiliation" will open a modal (C) which allows a user to move between affiliations. To change affiliations at any time navigate back to the "home" page.

3. Affiliation Management

i. Setting up an Affiliation

To request to set up a new Affiliation the Coordinator should email the help-desk at [email protected], and provide the following information:

Name of the Affiliation
Name and email address of the Coordinator
First name, Last name and email address for all members of the affiliation. These should be the email addresses to be used for interface registration.
Whether the Affiliation will need to submit Interpretations/Classifications to the ClinGen website (clinicalgenome.org)

ii. Managing an Affiliation

All management of the Affiliation should be done by the Coordinator. Including:

Making sure all members are registered to use the interfaces
Making sure all members are trained in the demo interface before entering data into the production database
Making sure all information about the Affiliation is up-to-date

iii. Updating an Affiliation

NOTE: All communication about updating an Affiliation must come via the Coordinator (e.g. new members, removing members, changing the name of the Affiliation, etc.)

GENERAL NAVIGATION

1. Dashboard view

a. Dashboard home – available from all pages

b. Navigating to “Select Variant for Variant Curation” – available from all pages

c. Navigating to “Create Gene-Disease Record” (described below) – available from all pages

d. Navigating to the online Help documentation – available from all pages

e. Navigating to “Select Variant for Variant Curation”

f. View a list of all Variant Interpretations – This list contains all the Interpretations curated to date, along with their status, creator, date created and date last edited.

g. Navigating to “Create Gene-Disease Record” (described below)

h. View a list of all Gene-Disease Records – This list contains all the Gene-Disease Records curated to date, along with their status, creator, date created and date last edited.

i. View of a curator’s recent history – This section provides a chronological history of all edits made by a curator within both the Gene and Variant Curation Interfaces. A curator only views their own history. Each highlighted text is a direct link to the relevant section of the Gene or Variant Curation Interface a curator was previously curating.

j. View of a curator’s current Variant Interpretation curation records – This section provides a list of edits made by a curator within the Variant Curation Interface. A curator only views their own Interpretations. Each highlighted text is a direct link to the variant a curator was previously curating.

k. View of a curator’s current Gene-Disease curation records – This section provides a list of edits made by a curator within the Gene Curation Interface. A curator only views their own Gene-Disease Records. Each highlighted text is a direct link to the Gene-Disease Record a curator was previously curating.

l. Download the complete or filtered Gene-Disease curation records or Variant Interpretations listed as a .csv file.

m. Logout – available from all pages

n. Filter the Gene-Disease Records or Variant Interpretations by Variant/Gene, disease, or mode of inheritance.

o. Filter the Gene-Disease Records or Variant Interpretations by curation status.

SELECTING A VARIANT FOR VARIANT CURATION

1. Begin variant curation

Select “New Variant Curation” in the top right of the interface. Enter the Variant ID using either the ClinVar Variation ID or a novel variant that you have registered with Baylor’s ClinGen Allele Registry. Click "Retrieve" and confirm that it is the correct variant. Then select "Save and View Evidence".

2. Variant titles

HGVS variant titles are determined according to the following preference order:

A canonical transcript is based on the transcript with the longest translation with no stop codons OR if there’s no translation, the longest non-protein-coding transcript. If a single canonical transcript is not discernible, the HGVS is based on the GRCh38 genomic coordinates.

If you hover over the “I” to the right of a variant title then text will appear that will explain how a title was derived.

3. Evidence View

You will now be in the “Evidence View” for the selected variant (see next section)

GENERAL ORGANIZATION OF EVIDENCE (EVIDENCE VIEW PAGE)

1. Evidence tab organization

The Evidence View is viewable by any logged in curator and includes both aggregated external evidence and evidence curated manually by individual curators.

Once you are in the “Evidence View,” you will see the information and evidence for the selected variant is organized into six tabs, Basic Information, Population, Variant Type, Experimental, Segregation/Case, and Gene-centric with different types of information and evidence.

2. Subtab organization by variant type

The Variant Type tab contains subtabs such that you can look at the appropriate evidence and evaluate the appropriate criteria according the to the variant type (Missense, Loss of Function, Silent & Intron, and In-frame indel).

EVIDENCE AND INTERPRETATION VIEWS

Once you have selected a variant, there are different viewing modes:

Evidence View (see previous section)
Interpretation
Interpretation with Disease Association
Curation

1. Evidence View

(see previous section for tab organization) Note: The Evidence View is viewable by any logged in curator and includes both aggregated external evidence and evidence curated manually by individual curators. In this mode, you can view all the evidence associated with a variant, clicking between tabs (see above). The ACMG criteria do not appear in this mode.

The Evidence View mode displays two main types of evidence, all curators in the VCI can see all evidence.

1. External evidence

The curation interface aggregates dozens of types of evidence from external resources such as gnomAD, PAGE, REVEl, ESP, ClinVar, dbNSFP, etc.

2. Manually curated evidence

Any evidence a curator enters for a PubMed ID (PMID) when in Interpretation mode (see next section) will be viewable by all curators in the Evidence View. Note: Evaluations (i.e. PS4 “Met”) and Interpretations are specific to the curator who makes them and are not currently viewable by anyone other than the curator who made them. See below for information on manually adding Case Segregation Data and Functional Data evidence types.

2. Interpretation

Note: An interpretation is specific to the curator who creates it and can only be viewed or edited by that curator or the affiliation the curator is curating under. This means that evaluations of the various criteria codes and the value of the interpretation (e.g. pathogenic) are specific to the curator who makes them and cannot be viewed by other curators.

To begin an Interpretation in which you can evaluate the evidence according to the ACMG criteria, select “Interpretation +”. If you had previously begun an interpretation for this variant the VCI will direct you to that entry. You may have one interpretation per variant in the VCI.

You will then be asked to agree to the VCI "Variant Submission Policy", once you agree to that you will be in Interpretation mode.

Once in Interpretation mode, the following will appear:

a. “View Summary” button to view a Summary of all the evaluations

b. “Disease +” and “Inheritance +” buttons for associating a Disease and Mode of Inheritance with the variant

c. Interpretation Progress bar that indicates the strength of criteria met and the calculated pathogenicity

d. Criteria bar - i) scroll over individual criteria codes to see a description for each criteria and ii) click on individual criteria codes to link to pertinent section in the VCI

e. The ACMG criteria evaluations where you can indicate whether an individual criterion is “Met” (see next section, “Evaluating Criteria”)

3. Curation Checkboxes on Tab Pages

If you have evaluated all the evidence on a particular tab page to your satisfaction, you can click the checkbox at the bottom of the tab page (for the Variant Type tab, this means you have evaluated any relevant subtabs to your satisfaction) and a check will appear on the tab for your reference. This checkbox will remain regardless of which tab you are on in the interface and can be unchecked as well:

MANUALLY ADDING GRANULAR EVIDENCE

1. Case Segregation Data

Coming soon...

2. Functional Data

Coming soon...

EVALUATING CRITERIA

1. Criteria placement & organization

Criteria are grouped according to the evidence required for their evaluation and on the appropriate tab page.

2. Criteria evaluation choices:

The pull-downs allow the following criteria evaluation choices:

• Not Evaluated: The default state of an Evaluation is “Not Evaluated”. This is the appropriate selection when there is no evidence to evaluate or the particular criterion is not applicable for the variant.

• Met: If the evidence supports application of a criterion, the curator should select “Met”. Curators should provide an explanation note for all Met criteria.

• Not Met: If the evidence reviewed does not support application of the criterion, the curators should select “Not Met.” Curators should provide an explanation note for all Not Met criteria.

• _Strong, _Moderate, _Supporting, _Very strong, _Stand-alone: The strength of evaluation for a criterion can be adjusted by selecting one of the above representations of the criterion (e.g. PM2_Supporting would be PM2 evaluated at the “Supporting” level rather than its inherent level, Moderate. Note: Benign criteria allow _Supporting, _Strong, and _Stand-alone adjustments. Pathogenic criteria allow _Supporting, _Moderate, and _Strong adjustments (except for PS2, which also allows _Very strong).

Benign pull-down choices – example:

Pathogenic pull-down choices – example:

3. Steps for evaluating a criterion or criteria:

• Examine evidence associated with criteria being evaluated

• Select an evaluation for all criteria related to the evidence from the pull-down

• Enter an explanation to support your selection

• Select Save

• Note that the button will now change from “Save” to “Update” – if you would like to change an evaluation, change it and be sure to click “Update” after. The update button appears as a visual clue that the criterion/criteria for that section have already been evaluated.

Note: When 2 (or more) criteria are opposites or cannot otherwise be “Met” at the same time, the interface will not allow “Met” to be selected for more than one of the criteria.

4. Criteria bar:

As you Save your evaluations, you will notice that the Criteria bar will indicate which criteria have been “Met” (solid color background with white criteria code), “Not Met” (grey background with colored criteria code), or remain “Not Evaluated” (white background with colored criteria code).

Clicking on a specific ACMG code will link to the pertinent section in order to evaluate that criterion.

5. Calculated Pathogenicity:

As you Save your evaluation, you will notice the Progress bar will indicate the number of criteria met according to the strength of the evaluation and whether they are Benign or Pathogenic. Additionally, it will automatically calculate the Pathogenicity each time you Save or update an evaluation:

The Calculated Pathogenicity outcomes are as follows:

Benign
Likely benign
Pathogenic
Likely pathogenic
Uncertain significance – insignificant evidence: there is not enough evidence to meet any of the above (1-4); there can be conflicting evidence
Uncertain significance – conflicting evidence: there is enough evidence to meet the above (1-4), but some of it is conflicting

ADDING DISEASE & MODE OF INHERITANCE

1. Interpretation with Disease Association

When you are ready to evaluate disease-specific criteria for your Interpretation, click the “Disease +” button. Be sure you’ve saved your evaluations before clicking this button. You will see the "Add Disease" modal appear, enter the desired ID and click "Retrieve from OLS". Verify your disease term and click save. You can find further help on searching MONDO using the MONDO Search Help link.

Now you will see the disease term under the variant name in the gray title area and in the top right of the “My Interpretation" banner:

2. Free text option for Disease

It's highly recommended to use an ontology term, if there is no MONDO term then a free text term may be entered for the disease. If you are unsure about an appropriate disease term, please feel free to contact us at [email protected] and we will be happy to assist. The add free text modal allows you to enter a free text term (up to 100 characters in length). You must also provide either a set of HPO terms (preferred) and/or a Definition for the term you are entering. Please remember that if someone else enters a different phrase for the same ID, the interface will not be able to determine they are equivalent.

3. Interpretation with Mode of Inheritance

You can add the mode of inheritance by clicking the “Inheritance +” button. Then select your mode of inheritance, and a adjective (if desired) from

Now you will see the mode of inheritance term under the variant name in the gray title area:

EVALUATION SUMMARY

1. Viewing an Evaluation Summary

If you have evaluated all the evidence to your satisfaction, you can click the “View Summary” button in the grey header to view a Summary of all your evaluations:

Once in the Summary View, the “View Summary” button will change to a “Return to Interpretation” button. This can be used at any time to return to the “Evidence View”.

At the bottom of the Summary page, all the ACMG criteria are split into three separate tables according their evaluation status:

Criteria meeting an evaluation strength: for criteria with evidence that supports a positive evaluation of the criteria

Criteria evaluated as “Not met”: for criteria with evidence that does not support a positive evaluation of the criterion

Criteria “Not yet evaluated”: for criteria which have yet to be evaluated

These tables summarize the evaluations made for each criterion into the following fields:

• B/P: The color of these icons, red for pathogenic and purple for benign, indicates whether each criteria is pathogenic or benign. “Met” criteria have ticks in a circle, “Not met” have crosses in a circle, and “Not evaluated” criteria have an empty circle.

• Criteria: All of the criteria are listed using their ACMG criteria codes, and their color indicates their pathogenicity on a scale from ‘purple’ benign to ‘red’ pathogenic.

• Criteria Descriptions: Short descriptions to explain the ACMG criteria.

• Modified: ‘yes’ or ‘no’ indicates whether or not a criterion has been modified. If it has, then ‘purple down arrows’ indicate a benign modification, and ‘red up arrows’ indicate a pathogenic modification.

• Evaluation Status: Criteria are shown as “Met”, “Not Met” and “Not evaluated”. Additionally, “Met” indicates any modifications: _Strong, _Moderate, _Supporting, _Very strong, _Stand-alone.

• Evaluation Explanation: This shows the explanation provided by the curator when evaluating each criterion.

Above these Summary tables is an overview of the interpretation so far, including the pathogenicity calculations:

a. Calculated Pathogenicity – the pathogenicity calculated based on all the evaluations saved so far

b. Modified Pathogenicity – the pathogenicity selected by the curator

c. Disease – shows a disease where one has been associated with the variant

d. Mode of inheritance – shows inheritance type where one has been associated with the variant

e. Modify Pathogenicity – pull-down which allows curator to select the pathogenicity

f. Explain reason(s) for change – allows curators to add free text to explain why they have selected an alternative pathogenicity to the one calculated

g. Evidence Summary – this free text box allows curators to summarize their evidence and provide a rationale for the clinical significance. This text accompanies the variant classification when submitted to ClinVar. It should include a description of the criterion and why they were met / not met supported by PMIDs or other evidence as appropriate.

h. Save – must be clicked to save a modification to the pathogenicity and/or a change in the status of the Interpretation

If the curator decides to select an alternative pathogenicity to the one calculated, they can do so by selecting an alternative option from the “Modify Pathogenicity” pull-down (e), however they must provide a reason for the change in the free text box (f) provided. The ‘Modified Pathogenicity’ (b) will only change to the new modified pathogenicity when the Save’ button (h) is clicked.

SAVING AN EVALUATION SUMMARY

1. When to Save a Summary

You will need to Save the Evaluation Summary:

if you want to Save any any edits made to the "Modify Pathogenicity", "Explain reason(s) for change", and/or "Evidence Summary" fields
if you want the option of making a Provisional Interpretation based on the current evidence/evaluations

Every time a curator updates evidence and/or evaluations they will need to re-click the Save button if they wish to make a Provisional Interpretation based on their new Summary.

2. In Progress Status

The first time an Evaluation Summary is Saved the status of the Interpretation will change to "In Progress". The Interpretation will remain "In Progress" until a Summary is Saved as Provisional.

3. Saving New Summaries

Every time the Save button is clicked in the Evaluation Summary any previous Summary is overwritten and the ‘Interpretation Last Edited’ is appended with a "New Saved Summary" label

SAVING AS PROVISIONAL AND APPROVED

1. What do Provisional and Approved mean?

Provisional

Provisional is used by curators to mark their Interpretation as complete
Provisional Interpretations created by Affiliations are considered ready for their expert review
The option to save as Provisional appears after saving an Evaluation Summary

Note: In future, it is intended that when an Interpretation is Saved as Provisional that it will be viewable by all other users (there will be an opt out) but this feature is not yet in place.

Approved

Provisional Classification has passed the review and approval process
The option to Save as Approved appears after saving an Interpretation as Provisional
Some Affiliations may require final ratification by a designated Approver, in which case the curator must select the name of the Approver from a pre-populated pull-down
Users working independently can choose to Approve their Interpretations whenever they wish.

Note: In future, it is intended that curators will be able to submit an Approved Interpretation to ClinVar but this feature is not yet available.

2. Approval Process Workflow

This diagram, for reference in reviewing the sections below, illustrates the possible Approval process workflows:

3. Saving as a Provisional Interpretation

Likely Pathogenic and Pathogenic Warning

NOTE: Likely Pathogenic and Pathogenic Interpretations must have a disease associated with them in order to Save them as Provisional. If you Save an Evaluation Summary for a Likely Pathogenic or Pathogenic Interpretation with no associated disease then the interface will provide you with a warning message to advise you to go back to your Interpretation to add a disease.

How to Save as Provisional

Upon saving a modified pathogenicity and/or changing/updating the Evidence Summary text then the ‘Save’ button will change to an ‘Edit’ button and an orange “Save Interpretation as Provisional” text will appear.

a. Edit button – clicking this will allow a curator to make further edits the Evaluation Summmary

b. ClinGen Affiliation – if the curator is curating as part of an Affiliation then this field will be auto-filled

c. Provisional Classification entered by – upon Saving the Provisional Interpretation this field will auto-fill with the name of the curator

d. Date Reviewed – a curator can optionally enter a review date from the calendar. Note: Dates in the future should never be selected!

e. Additional Comments – optional field for capturing additional notes about the review process

f. Preview Provisional – must be clicked in order to initiate the process for Provisionally Saving the Interpretation

Provisional Preview

NOTE: Once an Interpretation has been Saved as Provisional this action cannot be undone, so when the Preview Provisional is clicked the Provisional panel enters a Preview mode and offers the curator three options:

Cancel Provisional - this cancels the Saving as Provisional process
Edit - this allows the curator to go back and correct any errors (e.g. in the Additional Comments)
Submit Provisional - this will permanently Save the current Interpretation as a Provisional Interpretation

Current New Provisional

Upon Saving a new Provisional Interpretation it will appear at the top of the "Saved Provisional and Approved Interpretation(s)". The current Saved Provisional Interpretation will always be marked with a green flag.

New Saved Provisional Interpretations

Every time a curator updates an Interpretation (e.g. new evidence, new evaluations, etc.) they can choose to Save the updates by clicking the Save button in the Evaluation Summary. They will then be invited to Save that new Interpretation as Provisional.

Archiving Provisional Interpretations

Upon Saving a New Provisional Interpretation then that will now be the new current Saved Provisional and will appear at the top of the "Saved Provisional and Approved Interpretation(s)" panel and be marked with a green flag. The previous current saved Provisional Interpretation will now become archived, and its green flag will be replaced with a grey archive box.

4. Saving as an Approved Interpretation

How to start Approval Process

When a Provisional Interpretation is Saved then an orange "Approve Interpretation" panel will appear above the "Saved Provisional and Approved Interpretation(s)". This panel enables a curator to begin the process of Approving the current Saved Provisional Interpretation, i.e. the one marked with a green flag

If a curator navigates away from the Evaluation Summary page, then when they return they will still have the option of starting the Approval process for the current Saved Provisional Interpretation. To do so they should simply click on the orange "Approve this Provisional Interpretation" button found within the current Saved Provisional Interpretation.

Saving as Approved

All Approvals are processed via the orange Approve Interpretation panel:

a. ClinGen Affiliation – if the curator is curating as part of an Affiliation then this field will be auto-filled

b. Entered by – upon Saving the Provisional Interpretation this field will auto-fill with the name of the curator

c. Approver - if no Approver(s) have been identified by an Affiliation then by default this field will contain the name of the Affiliation, however if Approver(s) have been identified then the name of an Approver who has agreed the Approval must be selected from a pull-down

d. Date Approved – a curator can optionally enter an approval date from the calendar. Note: Dates in the future should never be selected!

e. Additional Comments – optional field for capturing additional notes about the approval process

f. Preview Approval – must be clicked in order to initiate the process for Approving the Interpretation

g. Green flag – indicates the current Provisional Interpretation can that be Approved

Approval Preview

NOTE: Once an Interpretation has been Saved as Approved this action cannot be undone, so when the Preview Approved button is clicked the Approval panel enters a Preview mode and offers the curator three options:

Cancel Approval - this cancels the Saving as Approved process
Edit - this allows the curator to go back and correct any errors (e.g. in the Additional Comments)
Submit Approval - this will permanently Save the current Interpretation as an Approved Interpretation

New Saved Approved Interpretation

Upon Saving a new Approved Interpretation it will appear at the top of the "Saved Provisional and Approved Interpretation(s)". The current Saved Approved Interpretation will always be marked with a green flag.

5. Saving a New Provisional Interpretation after Approval

If there is already an Approved Interpretation when a new Provisional is Saved then it will appear above the Approved Interpretation in the "Saved Provisional and Approved Interpretation(s)" panel, and the interface will provide the option of Approving the New Provisional Interpretation by displaying the Approve Interpretation panel.

6. Viewing Provisional and Approved Summaries

How to View Summaries

Upon saving all Provisional and Approved Interpretations a snapshot of their Evaluation Summary is also saved. A Summary is viewable for each Interpretation from the "Saved Provisional and Approved Interpretation(s)" on the Evaluation Summary page by clicking on the "View Provisional Summary" and "View Approved Summary" buttons. For archived Interpretations these buttons appear gray but they are still active linkouts to the Summaries.

Summaries

A Summary snapshot will contain a Summary table at the top with information about the Interpretation, followed below by the Evidence Summary, and finally the criteria tables underneath.

Printing Summaries

You can print an Interpretation Summary by using the Print PDF button in the footer.

When printing an Interpretation Summary we recommend the following print settings:

• "Landscape" for layout

• 50% for Scale

• "Minimum" for Margins

• Select "Background graphics"

You can also use your Print dialogue box to save your Interpretation as a PDF.

Feedback and Comments? Please email us at: [email protected]