ClinGen Registered User Login

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

Login Troubleshooting

Please confirm that:

1. You've authenticated your email by receiving and entering the sent code. Note, codes may take a few minutes to appear in your email inbox.

2. You are on the correct site (Test or Production).

3. You are using the right email address with correct capitalization. Note that Username is case-sensitive, so "Curator@clinicalgenome.org" is NOT the same as "curator@ClinicalGenome.ORG"

4. Your account has been activated. Note that new production site accounts require validation in a manual approval process. Please allow up to three business days after registration for account activation.

If you still need assistance, email us at clingen-helpdesk@lists.stanford.edu.

To create a new account or log into an existing account, click Login from the landing page of the test or production interface.

If you have an account and are unable to log in, see #login-troubleshooting

For assistance with creating a new account, see the next section, Registration

Landing Page

When you first login, you will be on the landing page, which contains general information about ClinGen and the VCI and GCI. To access your curations, head to the dashboard.

Dashboard View

Navigation Bar

Available from all pages. From here you can:

Affiliation Bar

Header

Displays the account and affiliation you are logged in under.

Tool Bar

To select which curation table(s) to display on the dashboard.

My ClinVar Submission Batches - This displays both current and closed ClinVar submission batches for the selected affiliation. Note: This option only appears when logged into an affiliation.

Curation Tables

• By default, the dashboard will open to My Variant and Gene Interpretations.

• All tables have similar functionality. Users can:

  • Search/filter on any text in any text field

  • Download the table as a .csv file

  • Navigate with pagination features and expand the number of curations displayed at once (up to 100)

• The My Variant Interpretations and My Gene-Disease Records tables have additional detail and functionality.

  • Columns for status, classification, met criteria (variant only), and date last modified

  • Ability to filter by status (In Progress, Provisional, Approved and Published)

Begin Curation

For assistance with the VCI, click Next, or go to:

For assistance with the GCI, go to:

ClinGen has two distinct curation interfaces, the Test Site and the Production Site.

The two sites have the same functionality, but there are important differences.

The Test Interface

https://curation-test.clinicalgenome.org/

The test site (also called the demo site) is intended as a resource for new curators and others wishing to familiarize themselves with the interfaces. All data is periodically deleted, and as such, this site should NOT be used for "real" curation.

The Production Interface

https://curation.clinicalgenome.org/

Data entered into the production interface is permanently saved, so this interface should only be used for “real” curation.

We recommend curators become familiar with the curation interfaces by exploring the test versions before curating “real” evidence in the production interfaces. Data entered into the test interfaces is erased annually, so do NOT enter any data you wish to be permanently saved.

The ClinGen variant curation process combines clinical, genetic, population, and functional evidence with expert review to classify variants into one of five categories according to the ACMG guidelines. Approved variant interpretations are published to the ClinGen Evidence Repository (ERepo) and to ClinVar.

The Variant Curation Interface (VCI) supports community curation and is available to any interested curator. For information on how to register, see Account Creation and Login.

The VCI supports the ClinGen FDA-recognized curation workflow, summarized in the diagram below:

For more information about ClinGen variant curation, please contact the Variant Curation Working Group at variantcuration@clinicalgenome.org.

What is an Affiliation?

An Affiliation is any set of people collectively curating together. This includes ClinGen groups (e.g. ClinGen Working Groups, ClinGen Expert Panels, Research Labs, Clinical Labs, etc.) and non-ClinGen groups. Once logged into an affiliation all curators can collectively:

1. Edit and score/evaluate evidence

2. Work on the same classification/interpretation

3. Approve the same classification/interpretation

Select and Change Affiliation

If a user is a member of at least one Affiliation, after logging in they can select any affiliation they are a member of to curate in, in which case all actions they take will be attributed to the selected Affiliation.

The current affiliation is always displayed in the dark blue Affiliation Bar; this is also where you can change affiliations. Note that the user's name is only displayed while not associated with an affiliation.

From the Dashboard:

From within the VCI or GCI:

Affiliation Management

Setting up an Affiliation

• Name of the Affiliation

• Name and email address of the Coordinator

• A list of currently registered users to be added to the affiliation (first name, last name, email address).

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 test interface before entering data into the production database

• Making sure all information about the Affiliation is up-to-date

Updating an Affiliation

When to Register

We recommend curators become familiar with the interface by exploring the test interface before curating “real” evidence into the production interface.

How to Register

We have two sites, the production site at and the test site at .

Each site requires its own registration (i.e. registering for one site does not create an account for the other).

The email address you register with will be your username.

To register for either site:

Click Login in the upper right corner.

Click Create Account in the sign-in screen.

Fill out the form and click Create Account to submit the request.

• The test site will automatically add you as a curator.

Begin variant curation

1. Select “New Variant Curation” in the top right of the interface.

2. Enter the Variant ID using either the or the ; please note the Allele Registry allows for novel variants to be registered by users.

3. Click "Retrieve" and confirm that it is the correct variant.

4. Then select "View Evidence" to enter Evidence View.

You will now enter Evidence View.

To add the mode of inheritance click which opens the Inheritance selection screen.

Select mode of inheritance, and then, if applicable, select an adjective.

After saving, you will see the mode of inheritance under the variant, and the Inheritance button will be teal.

Enter interpretation mode

To begin an Interpretation in which you can evaluate the evidence according to the , select from the evidence view.

You will then be asked to agree to the VCI Submission Policy Agreement:

Click Agree to enter interpretation mode.

If you select Disagree, you will return to evidence view.

Evidence tab organization

The Evidence View is accessible to any logged in curator. It includes both aggregated external evidence and evidence curated manually by individual curators. Please note: you cannot curate from the evidence view .

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

The Variant Type tab is further divided into four subtabs: Missense, Loss of Function, Silent & Intron, and In-frame Indel.

Variant Titles

Evidence types

The Evidence View displays two main types of evidence.

1. External Evidence

2. Manually curated evidence

Note: Evaluations (e.g. PS4 “Met”) and Interpretations are specific to the curator who makes them and are not viewable in the Evidence View.

Criteria placement & organization

The ACMG criteria are grouped in the VCI according to the evidence required for their evaluation. To evaluate them curators must navigate to the appropriate tab:

Each of the VCI tabs with criteria codes also supports users in manually adding Curated Evidence.

Criteria evaluation options

The pull-downs allow the following 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 meets the specified rules for a given criterion, the curator should select “Met”. Curators should provide an explanation note for all Met criteria.

• Not Met: Not met can be applied if:

  • No evidence is identified for the criterion, OR

  • There is evidence, but it is not sufficient, OR

  • Another mutually exclusive criterion has been met.

  Curators should provide an explanation note for all Not Met criteria.

• Strength: The strength of evaluation for a criterion can be adjusted by selecting a strength from the pull down menu for a specific criterion.

Steps for evaluating a criterion or criteria:

1. Examine evidence associated with criteria being evaluated

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

3. Enter an explanation in the free text box to support your selection

   • See Standardized Text for ClinGen Variant Curation Expert Panels

4. Click Save

Curation Checkboxes

At the bottom of each tab which includes criteria for evaluation, you will see the following checkbox:

If you have evaluated all of the evidence on a particular tab to your satisfaction, you can click the checkbox and a check will appear on the tab for your reference:

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).

Additionally, the Progress Bar will automatically calculate the pathogenicity each time you save or update an evaluation

Auto-calculated Classification

The calculated classifications follow the ACMG/AMP 5 tiers and are as follows:

1. Benign

2. Likely benign

3. Uncertain significance

4. Pathogenic

5. Likely pathogenic

To add a specification document click on the button.

The drop down menu will display all specification documents that are applicable to the ClinGen approved VCEP you are curating as a part of.

If you are not curating under an affiliation, all current specification documents are displayed.

Layout of the Add Evidence Details window

• The evidence source is indicated in the first line.

  • Details entered in the "Add [Source] Evidence" selection screen do not appear.

• All ACMG criteria codes in the Case/Segregation tab have associated fields.

  • "#" fields accept numerical input only

  • For PP4, HPO terms only

• Fields relevant to the specific criteria code will be noted with a green background.

• There are optional free text "Comment" fields associated with each data point, as well as an "Additional Comments" field at the end.

Each record has a viewable audit trail displaying which curator performed which actions at which time.

To access the audit trail, click on the button.

The audit trail is organized in reverse chronological order (i.e., the most recent records are listed first) and is only viewable by the record owners (either an individual or all members of an affiliation). The audit trail can also be searched.

Once you have evaluated all the evidence to your satisfaction, click to view a Summary of all your evaluations:

The Summary View has two sections.

1. Evaluation Summary

2. Three tables displaying ACMG criteria, divided according to evaluation status

To select an alternative classification:

1. Select the appropriate option from the Modify Classification pull-down.

2. Provide a reason for the change in the free text box.

3. Click

After saving the modified classification and reason for change, the Evaluation Summary will update.

Case/Segregation Tab Organization

A. If no curated evidence has been associated with this variant, the ACMG criteria codes for evaluation immediately follow the yellow box. Curated Evidence may be associated with the following individual and pairs of criteria (from top to bottom): BS2, PS4, BS4/PP1, PM6/PS2, BP2/PM3, BP5, and PP4.

B. If curated evidence has been added (to the current interpretation or a prior one), a table summarizing all entered evidence will appear before the criteria codes. This table will auto populate with any new submitted evidence.

Adding Curated Evidence

Scroll down or select a criterion from the Criteria Bar.

Evaluation of criteria may be completed before or after adding Curated Evidence.

Before adding evidence, you must select an evidence source.

Choose an option from the "Select Source" pulldown

Available fields vary based on the source:

The first field is required (indicated with *). Additional fields are optional.

Structured Narrative of Functional Impact is found under the Experimental Tab, in the Experimental Studies section.

In most cases, this field will display "No evidence added."

This field is not directly editable in the VCI. For more information visit:

How to start Approval Process

After a Provisional Interpretation is Saved, 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.

If a curator navigates away from the Evaluation Summary page, 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 this field will autofill, otherwise it will be blank.

B. Entered by: After clicking "preview approval" this field will auto-fill with the name of the curator.

C. Select Approver: Approver(s) identified by the Affiliation will be listed in the pull-down. An approver must be selected to proceed.

D. Final Approval Date: By default, this populates with the current date. A curator can optionally enter a PAST date from the calendar. Note: Dates in the future should never be selected!

E. Approver Comments: Optional field for capturing additional notes about the approval process.

F. Preview Approval: Click to initiate the process to Approve the Interpretation.

Approval Preview

In Preview mode the curator has three options:

1. Cancel Approval - this cancels the Saving as Approved process

2. Edit - this allows the curator to go back and correct any errors (e.g. in the Additional Comments)

3. Submit Approval - this will permanently Save the current Interpretation as an Approved Interpretation

New Saved Approved Interpretation

After clicking Submit Approval, the new Approved Interpretation 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. Older Approved Interpretations are noted by a grey archive box.

The curator will also be presented with publishing options (see Publishing from the VCI)

How to Save as Provisional

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

B. ClinGen Affiliation: If the curator is curating as part of an Affiliation, this field will display that affiliation. If not curating as part of an Affiliation, it will display "--"

C. Provisional Classification entered by: Field will auto-populate with curator's name after clicking "Preview Provisional"

D. Date Reviewed: Field will auto-populate with current date. Curator may also enter a date manually (MM/DD/YYYY) or select 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

Provisional Preview

In preview mode, the curator has three options:

1. Cancel Provisional Returns to prior view and cancels the Saving as Provisional process. Any additional comments will be deleted, and the Date reviewed returns to the current date.

2. Edit Returns to prior view and allows the curator to go back and correct any errors. Additional comments and date changes are saved.

3. Submit Provisional Permanently saves 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.

VCI users can potentially publish an approved interpretation to two external repositories:

• The ClinGen Evidence Repository (ERepo)

  • Available to fully approved ClinGen VCEPs

  • Process is API-driven (automated)

• ClinVar

  • Available to users curating as part of any affiliation

  • Process is manual (data is downloaded to spreadsheet)

  • Option for both individual variant and batch submissions

Both publishing options are available via the Summary Page.

Evaluation Summary

The first section provides a summary of the variant classification (auto-calculated and modified), disease association, mode of inheritance, and any associated specification document.

Following the summary information, there are three fields available to edit:

A. Modify Classification: pull-down which allows curator to select the pathogenicity

B. Reason(s) for change: free text box for curators to explain why they selected an alternative pathogenicity to the one calculated

C. Evidence Summary: free text box for curators to summarize their evidence and provide a rationale for the clinical significance

Criteria Tables

At the bottom of the Summary page, all of the ACMG criteria are split into three separate tables according their evaluation status. These tables are not editable in Summary View. To make changes, you must return to Interpretation Mode.

Criteria meeting an evaluation strength

Criteria evaluated as 'Not met'

Criteria 'Not yet evaluated'

Each table summarizes the evaluations made for each criterion into the following fields:

• B/P: Red icon indicates pathogenic; purple icon indicates benign. “Met” criteria have ticks in a circle, “Not met” have crosses in a circle, and “Not evaluated” criteria have an empty circle.

• Criteria: Listed using their ACMG criteria codes; color indicates pathogenicity on a scale from ‘purple’ benign to ‘red’ pathogenic.

• Criteria Descriptions: Brief descriptions of the ACMG criteria.

• Modified: For "met" criteria, ‘yes’ or ‘no’ indicates whether the criterion has a modification. "Not met" and "Not evaluated" criteria will display N/A.

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

• Explanation: Displays criterion-level explanation provided by the curator.

The Variant Prioritization (VP) is a VCI feature requested by ClinGen Expert Panels curating variants to enable the discovery of prioritized variants for curation through filtering on select variant evidence data. Ultimately we plan for the VP to also support the sorting, updating and batch transfer of prioritized variants for curation at a larger scale within the VCI.

Once in Interpretation mode, the following options will appear:

A. Click to view a summary of all criteria evaluations.

B. Click to view the complete history of curation actions for this interpretation record. Note: It will not include actions from other interpretations of this variant.

F. The Progress bar indicates the strength of criteria met and the auto-calculated pathogenicity.

G. The Criteria bar displays all ACMG criteria codes. Scroll over a code to display its description. Click on a code to navigate to the pertinent section in the VCI.

The Evidence Tabs will now be populated with the ACMG criteria evaluations where you can indicate whether an individual criterion is “Met” (see Evaluating Criteria).

Any user with an active curation interface login can access the VP. The VP can be accessed from the ClinGen VCI production interface. Select VP features for saving searches are restricted to users logged in as an affiliation.

To access the VP from within the interface, click on the “Variant Prioritization” button in the blue navigation bar.

Following the evaluation of each criterion (or group of criteria), curators may include associated Curated Evidence.

• The Population, Variant Type, and Experimental tabs include fields to add Curated Literature Evidence by PMID.

• The Case/Segregation tab (see next section) includes Curated Evidence fields which allow for additional types of evidence (e.g. Clinical Lab).

Add Curated Literature Evidence

Navigate to the criteria evaluation to which you wish to add literature evidence.

Click "Add PMID" to open the "Add new PubMed Article" selection screen.

Enter PMID and click "Retrieve PubMed Article."

Confirm the retrieved citation is correct and click "Add Article."

The citation will now appear under Curated Literature Evidence.

Select the appropriate criteria code from the pulldown menu and enter a description of relevant data in the "Evidence" text box.

Click "Add Evidence". Note, both fields must be completed to proceed.

The literature evidence is now added to the evaluation along with the curator's name (and affiliation if applicable) and date/time added.

If you wish to change the criteria code or revise the evidence text summary, click Edit.

If you would like to remove the article completely, click Delete. You will be prompted to confirm deletion and have the option to cancel if you clicked delete in error.

You may now move on to evaluate other criteria, or click Add PMID to add additional article(s) to this section.

ClinVar

VCI users curating as part of any affiliation can use the "ClinVar Submission" buttons on their approved interpretation snapshot to generate data that can be submitted to ClinVar via spreadsheet.

The Batch Submission option was introduced in November 2022.

Batch submission process

Click on Add to Current Batch to add a variant to a batch

Note, if this is the first variant added, a new batch will be created and named with current month and year

The batch name will be added to the Publishing Status for the variant.

Click on the Batch name to view the current and closed ClinVar Submission Batches for the Affiliation.

Once all desired variants have been added to the batch, click Generate Submission Data, which opens the ClinVar Submission Data window.

Click Generate. Once the data populates, click Copy (to clipboard).

The data can now be pasted into a spreadsheet and submitted in the ClinVar submission portal.

Once the data has been submitted to ClinVar, click the Edit button to open the Edit Current Batch window.

Change the Status from "In Progress" to "Submitted to ClinVar." The Date Submitted field will now be available to edit and a Warning will appear.

You must type "Confirm" into the text box to proceed. Then click the Save button to close the batch.

The submission batch will now be listed under Closed Batches on the affiliation's ClinVar Submission Batches page.

The Publishing Status of all variants in the batch will be updated to "Closed Batches."

Searches on the VP are currently based on the HGNC gene name. A list of all supported genes is displayed under the search bar on the search page. The VP will return all variants for the given gene identified to ClinGen’s Allele Registry, along with their associated data. This search process may take a few minutes.

Each variant curation record may be associated with one disease, one mode of inheritance, and one specification document. Each of these may be selected and modified while the record in is in progress by using the grey boxes in the interpretation progress bar.

The filter view has the following sections:

a Displays the search term(s) used

b Displays the filters applied

c Toggle the "Columns" section to control the data displayed in the "Selection" section

d Use the "Add Filter" button to add new filter(s)

e The Filter Progress Bar shows how many variants were initially selected for, how many match and don't match the applied filters, and how many variants are actively selected in the selection section.

f The Selection section displays the data for filtered upon variants and enables specific variant selection.

When to Save a Summary

You will need to Save the Evaluation Summary:

1. If you want to Save any any edits made to the "Modify Classification", "Explain reason(s) for change", and/or "Evidence Summary" fields, OR

2. If you want the option of making a Provisional Interpretation based on the current evidence/evaluations.

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.

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.

The VP "Columns" view allows a user to customize the table output they see. Users can drag and drop reorder the column display, add or remove columns, and fine tune which data is displayed.

The VP supports the following filters: ClinVar Aggregated Clinical Significance, ClinVar Review Status, Molecular Consequences (limited to MANE select transcripts), gnomAD v.2.1.1 (subpopulations, total, male and female, and population filters for both exome and genomes), REVEL scores, and VCI interpretation status.

Filters can be added using the "+ add filter" button. Filter options are expanded using the right-handed arrow. Applied filters are displayed in the filter view.

Interpretation with Disease Association

When you are ready to evaluate disease-specific criteria for your interpretation, click or to open the "Add Disease" selection screen.

Enter the desired ID and click "Retrieve from OLS". Verify your disease term and click save.

Free text option for Disease

It's highly recommended to use an ontology term, but 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 contact us at clingen-helpdesk@lists.stanford.edu and we will be happy to assist.

Click on "Add free text term" to enter a free text term (up to 100 characters in length). You must also provide a set of HPO terms (preferred) and/or a definition for the term you are entering.

Once variants of interest have been identified, a user can select them using the checkbox on the left side of the main table.

Users can then use the orange 'Transfer' button to download the selected variants and associated data into a .csv output.

What do the different record statuses mean?

In Progress

• In progress is used for any record NOT in a provisional or approved status. It denotes records that are still being worked on and have not yet had a snapshot saved.

Provisional

• Provisional status is used by curators to mark their Interpretation as complete after saving an Evaluation Summary

• Provisional Interpretations created by Affiliations are considered ready for their expert review

Approved

• Approved status is used after 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.

Approval Process Workflow

The data in the VP originates from multiple sources, specifically: Ensembl, MANE, gnomAD, myvariant.info, ClinVar and the VCI itself.

ClinGen-built tools such as the ClinGen Allele Registry, the Linked Data Hub, the Data Ingest Service and the ClinGen Data Streaming Service, along with a streaming microservice pull and collate the data for users in the VP to search, filter, and prioritize variants on.

To enter a free text term, click on the "Add free text term" link in the "Select Disease" selection screen.

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

Recommended print settings:

• Layout: Landscape

• Scale: 50%

• Margins: Minimum

• Background graphics selected

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

Curation Central is the landing page for each Gene-Disease curation. It has three main components: a top panel that displays information about the gene-disease record; a section showing the current classifications and a list of variants currently associated with the record; and a data entry section.

The top panel will remain at the top of the page during curation; it has the following components:

A. First line of the header shows the selected Gene Symbol and Disease Term

B. Second line of the header shows the Mode of Inheritance. If an adjective was selected, it will appear in parentheses

C. Link to Curation Central home – available from all pages

D. Link to the Disease edit tool

E. Link to a table to preview the currently scored evidence (opens in new tab)

F. View Classification Summary shows the classification matrix with the current scores – available from all pages

G. Gene symbol and links to the HGNC and NCBI Gene web pages

H. Disease name and links to MONDO and OMIM pages (if available; add a link to OMIM using the "Add+" link)

I. The name of the curator who first created the Gene-Disease record, the Affiliation under which the record was created, and the time when the record was first saved; followed by a list of all participants who have made edits to the Gene-Disease record and the curator name and timestamp for the most recently saved edits to the Gene-Disease record

The central panels show current classifications as well as all variants that have already been added to the curation. The "My classification" section reflects work within the Affiliation, while "Other classifications" show work outside the current Affiliation.

The bottom panel is the curation panel, where you can begin to add evidence, starting with adding PubMed articles.

The ClinGen Evidence Repository (ERepo)

Fully approved ClinGen VCEPs can publish their approved interpretations to the ERepo via the summary page.

Click the Publish to Evidence Repository button to open the "Publish Interpretation to the Evidence Repository" box.

You will be asked to select a reason, or reasons, for publishing the curation. This information will be used by the ERepo to designate the curation's version number.

If this is a new curation, please select "New Curation". This disables the other checkboxes as they are only applicable to previously published curations.

If this is a recuration, or you are publishing with a minor (administrative) update please select all relevant reasons.

Click the Preview Publish button to see a preview of the interpretation to be published.

Click the Publish button, and the data will automatically be published to the ERepo.

The summary page will update to reflect the published status, and the option to Unpublish from the ERepo will be available.

The curation interface provides spaces for entering information in the following formats:

• Dropdown menus: select the appropriate option; subsequent options in the curation interface may change depending on the choice

• Spaces for controlled vocabularies (e.g. approved gene names, ontology terms): consult the appropriate ontology; a link-out is provided

• Free text fields

For a subset of fields, entry of data or information is required; these fields are marked by an asterisk. If you attempt to save your work, but a required field has not been filled, an error notice will appear next to the Cancel/Save buttons, and any fields that require curation will be outlined in red.

Genetic and experimental evidence is collected from individual publications. The basic workflow for evidence collection is outlined here:

The Evidence panel on the right is the starting point for adding evidence for a selected article. To begin curation, click the ‘+’ sign next to the specific type of evidence you would like to curate.

To add a peer-reviewed, published PubMed article to the Gene-Disease record, click the “+ Add” button next to "Select Evidence Source" in the curation panel.

Enter the PMID into the selection screen that appears and click the “Retrieve Evidence Source” button.

Based on the PMID entered, the authors, title, and citation details will be retrieved. If these details are correct, add that PMID to the Gene-Disease Record by clicking the “Add Evidence Source” button. The PMID will now appear in the Curation Central view for that Gene-Disease Record. Additional articles can be added to the Gene-Disease Record in the same way.

All articles that have been added to the record can be found in a scrollable Evidence Source panel on the left-hand side, with all authors, title, citation details, and PMID shown for each article. By default, a newly added article will be the one selected for curation, as indicated by a blue border. To select a different article for curation, click on that article in the left-hand panel.

The evidence curation panel on the right-hand side provides access to curation resources for adding Genetic and Experimental Evidence from the selected article.

The central panel shows additional details about the selected article, including the full abstract and a link to PubMed. In addition, the panel provides space to enter notes on evidence in the paper that could not be scored, as well as for any other comments you might want to make. If the article provides the earliest report of a connection between the gene and the disease, select the button next to the "This is the earliest report..." text.

Select the "Save" button to save the notes and selection. If the notes need to be edited, select the "Edit" button, which will return the panel to the editable state.

As of August 8, 2024, the GCI now supports adding evidence from ClinVar submissions as well as published papers. ClinVar submissions can be added by querying the VCV and SCV record for a specific ClinVar variant.

The Variation ClinVar record or 'VCV' is the accession in ClinVar of aggregated data from all submitted records for classifications of the same variant. The number after the period in a VCV is the version of that particular variant accession. For example, VCV001679524.3 refers to version 3 of VCV001679524.

Further down the ClinVar variant page, this VCV record will also list all submissions related to that variant from different laboratories and research groups, each with their own Submitted record in ClinVar, known as an SCV.

'SCV' is the accession number assigned to a submitted record in ClinVar, e.g. SCV003931173.1.

The number after the period in the SCV is the version of that particular submitter accession. For example, SCV003931173.1 refers to version 1 of SCV003931173. If you submit a query to ClinVar based on that SCV, e.g. SCV003931173.1, you are directed automatically to the VCV page that includes this submitted record. The SCV accession number and version are displayed in the Submissions section.

Below is an example of what a ClinVar entry would look like in the GCI compared to a published PMID:

Both evidence sources can be added from the GCI landing page. The “Add” button will open a selection screen for retrieving and adding evidence.

After clicking the "Add" button, a selection screen will open. Users can search by PMID or ClinVar VCV ID (including VCV version number). To add a particular submitter's ClinVar entry to the GCI, enter their full SCV including the version number (for example, SCV003931173.1, not just SCV003931173).

To add a ClinVar submission as evidence in the GCI:

1. Click the “Add” button in the evidence source column.

   1. A new selection screen opens.

2. Enter ClinVar VCV ID (including version) in top field.

   1. A link to the VCV record will immediately appear.

3. Enter the SCV ID (including version) in the bottom field

   1. You can use the VCV link provided to find the SCV ID of the submitter you want to cite, if you don’t already have it.

4. Click the “Retrieve Evidence Source” button

   1. A preview of the ClinVar entry will appear below.

5. Click the “Add Evidence Source” button to add the ClinVar entry to the GCI

Based on the SCV entered, the Submitter, Variant title, date last updated and version number will be retrieved. If these details are correct, add that SCV to the Gene-Disease Record by clicking the “Add Evidence Source” button. The SCV will now appear in the Curation Central view for that Gene-Disease Record. Additional ClinVar submissions can be added to the Gene-Disease Record in the same way.

The ClinVar submission is now viewable and scorable in the GCI. Comments from the ClinVar submission appear where paper citations and abstracts normally would. Evidence can now be added and scored as usual.

Case-level genetic evidence can be entered for:

A group -- when there are many probands with similar characteristics in a single paper.

A family -- when you want to document specifics about multiple family members OR if you want to score segregation information.

An individual -- when you want to report a single proband.

These categories are not mutually exclusive, i.e. an individual can be part of a family or a group.

A single publication can be the source of multiple types of evidence. Variant evidence can only be scored on an individual. For example, you could start with a group as an easy way to document phenotype information shared by all individuals in the group, but you would need to further document each individual to be able to score variant evidence.

Case-Control genetic evidence can be added when statistical analysis is used to evaluate enrichment of variants in cases compared to controls.

NEW: GeneTracker ID is required to create a new gene-disease record!

Prior to creating a new gene-disease record (also known as a GDM, for Gene, Disease & MOI) in the GCI, pre-curation within the GeneTracker database is required. Pre-curation includes defining the disease (MONDO ID) and mode of inheritance and capturing the decision within the GeneTracker. A link to the GeneTracker is provided; it requires a separate login.

Only one record can exist in the GCI for each unique gene-disease-MOI pairing. If curation is desired for a GDM that already exists, it is customary to contact the Coordinator for the GCEP that created it to see if they are amenable to a transfer of ownership of that GDM.

A new gene-disease record is created by selecting the "New Gene Curation" button.

The GCI requires you to enter the HGNC gene symbol, the disease entity (MONDO ID), and the mode of inheritance (via pulldown options provided). An optional adjective that further describes the mode of inheritance can be selected from a list of options. In addition, you must enter the GeneTracker precuration ID, which can be found on the GeneTracker page (see below) and in the URL of the page.

The GCI will check the information you enter against the record in the GeneTracker. The gene, disease, mode of inheritance, and affiliation you are curating under must match with the GeneTracker information; if a mismatch is detected, the GCI will return an error message.

A link to the HGNC is provided, enabling you to confirm that you are using the approved gene symbol. Enter the gene symbol and select the appropriate mode of inheritance from the drop-down menu. For some modes of inheritance, an optional "adjective" or distinguishing characteristic that provides further detail can be added. For Disease/MONDO search help, please see this page.

Does variation in this gene cause disease?

ClinGen Gene-Disease Clinical Validity curation attempts to answer this question. The curation process (usually abbreviated to "gene curation") involves evaluating the strength of evidence supporting or refuting a claim that variation in a particular gene causes a particular disease. The final result of gene curation is a classification of the gene-disease pair into one of five categories depending on the strength of evidence:

• No Known Disease Relationship

• Limited

• Moderate

• Strong

• Definitive

Gene-disease clinical validity curation is led by gene curators from ClinGen Gene Curation Expert Panels (GCEPs). Curators first perform a pre-curation literature search to gather pertinent data from published articles. An important next step is to assign the correct disease (using MONDO disease ontology) by following the lumping and splitting criteria. This disease information must be curated into the ClinGen Gene Tracker tool prior to starting gene curation for each gene-disease pair.

​The gene curation process is performed in the Gene Curation Interface (GCI) and is restricted to curators who are affiliated with a GCEP. A gene-disease record is often referred to as a "GDM" - short for "Gene-Disease-Mode of Inheritance", the three required components of the record. Within each gene-disease record, the genetic and experimental evidence gathered from publications is evaluated and scored according to the gene-disease clinical validity classification framework that was developed by the ClinGen Gene Curation Working Group. The GCI assists curators by collating all the scored evidence and providing a calculated classification, but if required GCEPs can modify their classification. Once the GCEP has finalized their classification selection, they can provisionally save it, and pass it along for their expert review process. Upon successful review, the GCEP can approve their final classification and publish it to the ClinGen website.

A visual representation of the full gene curation workflow is shown below.

For more information about ClinGen gene curation, please check out the information on the https://clinicalgenome.org/curation-activities/gene-disease-validity/ website or get in touch with the Gene Curation working group at genecuration@clinicalgenome.org.

The top section of the curation interface shows the publication currently being curated.

Use this option for entering many individuals with similar characteristics from the same paper. All required fields (marked with a star) must be filled in before the curated record for a group can be saved. The required fields are:

• Group Label is a free-text identifier assigned by the curator. It should be used to uniquely identify a group described in a publication. If possible, use the identifiers that the authors use to label the group in the paper.

• Group -- Common Disease(s) & Phenotype(s) requires information in at least one of the two categories: Disease(s) in common (usually select “Copy disease term from Gene-Disease Record”) or Phenotype(s) in common (HPO terms or free text).

• Total number of individuals in the group

The Demographics section allows you to enter a variety of demographics information that describes the group. Please enter as many pieces of information as are available in the publication.

The Information section contains the final required field, "Total number of individuals in group". You can add a variety of additional information about the group if it is available in the publication.

In the Methods section, you can add information about methods used to obtain genetic data for the group, e.g. previous testing, genotyping, and associated methods.

The Additional Information section allows you to enter any other potentially relevant information about the group in a free-text format. If the same group is described in additional publications, you can enter the PubMed IDs of these publications in the space provided here.

The information entered here will only be saved upon clicking the blue "Save" button at the bottom of the page. If any required information is missing, a red warning label will appear and the missing fields will be highlighted in red.

Saving the group information returns you to Curation Central. The curation panel will now show the newly entered group; you can add or edit information by clicking on the "Edit" icon. If you need to add family and/or individual information for any family or individual in the group, you can simply select the appropriate button here.

The top section of the curation interface shows the publication currently being curated.

First, identify the type of experimental evidence presented in the publication. The following evidence types are supported in the GCI:

• Biochemical Function Evidence

• Protein Interactions Evidence

• Expression Evidence

• Functional Alteration Evidence

• Model Systems Evidence

• Rescue Evidence

For specific experimental evidence examples, see Appendix B of the .

Select the appropriate experiment type from the dropdown menu. Depending on this selection, different options for data entry will appear next.

Regardless of the experiment type, an experiment name is one of the required inputs. You can optionally associate a specific variant with each experiment. Finally, select whether the experimental evidence should be scored, brought up for review by the GCEP, or contradicts the gene-disease association.

It has recently come to our attention that the National Library of Medicine has been the use of Pubmed PMIDs for preprints from certain servers (bioRxiv, medRxiv, others).

Adding preprints as evidence to the GCI via PMIDs was never an intended use case of the current GCI’s PMID functionality. Addition of evidence via PMID is intended for peer-reviewed published evidence only.

Until the NLM pilot is guaranteed to be supported past the pilot phase, we are asking all users: please do not add PMIDs belonging to preprints to the GCI.

If a preprint contains data that is deemed clinically relevant for curation by expert panels:

• If scoreable: Note that the use of preprint data as evidence should be an extremely rare use case included at the GCEP’s discretion. Include preprint data in the evidence summary and manually adjust the classification if it is impacted by the inclusion of preprint evidence.

• If non-scoreable: please do not include the pre-print data in the evidence summary.

We plan to develop support for the addition of preprints as evidence via DOIs (not PMIDs), and will share updated guidance about this feature in a future version of the GCI.

The top section of the curation interface shows the publication currently being curated.

The "Curate Family Information" page is split into relevant sections based on the type of evidence. The first three sections are in a similar format to the same sections in the "Curate Group Information" page. All required fields (marked with a star) must be filled in before the curated record for a family can be saved. The required fields are:

• Family Label is a free-text identifier assigned by the curator. It should be used to uniquely identify a family described in a publication. If possible, use the identifiers that the authors use to label the family in the paper.

• Family -- Disease(s) & Phenotype(s) requires information in at least one of the two categories: Disease(s) in common (usually select “Copy disease term from Gene-Disease Record”) or Phenotype(s) in common (HPO terms or free text).

• Family -- Segregation requires information on the number of affected individuals with the relevant genotype.

In the "Family -- Demographics" section, use the drop-down menus to enter any information about family demographics that were provided in the publication.

In the "Family -- Methods" section, you can enter details about prior testing within the family and the genotyping method(s) used to establish that members of the family carry a variant in the gene of interest.

The "Family -- Segregation" section is composed of two subsections. The "Tested Individuals" section allows you to enter the number of affected/unaffected individuals with/without the genotype under consideration. In addition, if information on segregations within the family is available, you can enter this number here. An estimated LOD score will be calculated if the required number of segregations for the mode of inheritance is met and will be shown in the following "LOD Score" section.

The "LOD Score" section allows you to enter the LOD score if one was included in the publication. Selecting "Yes" in the "Published LOD score?" dropdown menu will enable you to enter the numerical value in the "Published Calculated LOD score" field.

If there is either a published LOD score or an estimated LOD score based on reported segregations, and if this score should be included in the final aggregate calculation, select "Yes" in the following dropdown menu.

A box is provided to add free text to "Explain reasoning" behind a decision to include or exclude a published LOD score. An additional free text box allows "Additional Segregation Information" to be entered.

Depending on your selection, the estimated or published LOD score will appear in the corresponding section of the Evidence Matrix and Scored Evidence summary.

The "Family -- Variant(s) Segregating with Proband" section enables you to associate a proband and the segregating variant with this family.

The "Proband Label" field is a free-text field and should contain information that uniquely identifies the proband. If possible, use the label given in the publication; do not use a real name.

The disease ID(s) for the disease(s) associated with the Family is automatically shown and can be copied to the proband. Alternatively, a different disease term can be selected.

The options for checkboxes presented below the disease term differ depending on the mode of inheritance. The example below shows the option for dominant inheritance; if the proband is known to be hemizygous, check the provided box. For recessive inheritance, you will have the option to indicate the presence of one homozygous variant or two variants in trans (see below).

To associate the relevant variant(s) with the proband, click the "Add Variant" button. For further information on adding variant information, see the Adding Variant Information section.

If you are scoring segregation without an associated proband in the GCI, note that once you have entered the information on a proband, if you do not enter a proband name and save, it will only associate the LOD score to segregation section only, and will not automatically associate a proband with the family. This may be accurate as some older literature on linkage analysis may have only talked about a family without a proband or identified variant. This would be categorized on the final gene curation record as “segregation without a proband.” However, if you do intend to associate a proband, please enter in a “proband name” when prompted, or if you forget, you can go to the GCI gene curation main page, choose the appropriate PMID, pick the family, and click the “add individual” button. See for example this RPE65 record.

The final "Family Additional Information" section allows you to enter any additional relevant information about the family. In particular, if the same family is described in any other publications, this could be noted here.

The top section of the curation interface shows the publication currently being curated.

All required fields (marked with a star) must be filled in before the curated record for an individual can be saved. The required fields are:

• Individual Label is a free-text identifier assigned by the curator. It should be used to uniquely identify an individual described in a publication. Please use any identifiers that the authors use for the individual or family in the paper (e.g. MRX69 Individual III-2). Never use a real name. In addition, labels must be different across publications. If the same identifier, such as “Proband 1”, is used across several publications, the system considers this to be the same individual, which will affect scoring and website display. Please use different labels for probands, for example by adding the first author name followed by the identifier in the paper (i.e. “Wang Proband 1”). Note that there is a limit of 60 characters.

• Is this Individual a proband is a dropdown menu that only allows a Yes/No selection. Answer “Yes” if you intend to count this person in your scoring.

• Disease for Individual becomes a required field if the individual is a proband; usually select “Copy disease term from Gene-Disease Record.”

• Sex

While not required, some fields are necessary to enable scoring. At minimum, you must enter a variant and provide the required information there (see the Adding Variant Information section).

The following section enables curation of the disease and phenotype(s) of the individual. If the individual is a proband, a disease entry is required, usually by selecting “Copy disease term from Gene-Disease Record.” All other fields are optional.

The following section enables curation of the demographics of the individual. The only required field is "Sex". The dropdown menu contains extensive options, including "unknown" if no information is provided in the publication. Additional information about the individual should be entered if it is given in the publication.

Curation of biochemical function evidence is based on two options that are selected from a pull-down menu:

• A. The gene product performs a biochemical function shared with other known genes in the disease of interest. The biochemical function of both gene products must have been proven experimentally, and not just predicted. When awarding points in this evidence category, the other known gene(s) should have compelling evidence to support the gene-disease relationship.

• B. The gene product is consistent with the observed phenotype(s).

The curation interface for both options has a number of required fields, shown with an asterisk next to the field. For both, the required fields are:

• Experiment name is a free-text field; please choose a descriptive name for the experiment.

• Identified function of gene in this record requires an entry in either the Gene Ontology (GO) ID or the free text field. To aid in searching for the correct GO ID, there are three links provided; one to view existing GO annotations for the gene product, one that links to the OLS GO search, and one that links to QuickGO. Only choose terms from the Molecular Function (MF) or Biological Process (BP) domains and terms that have manual experimental evidence codes associated with them, e.g. IDA, IMP, IGI, IPI or IEP.

• Evidence for above function is a free text field where you should describe the evidence supporting the function(s) you chose.

For option A, the additional required fields are:

• Other gene(s) with same function as gene in record requires entry of a valid HGNC gene name.

• Evidence that above gene(s) share same function with gene in record is a free text field where you should describe the evidence for shared function.

For option B, the additional required fields are:

• Phenotype(s) consistent with function requires an entry in either the HPO or free text fields.

• Explanation of how phenotype is consistent with disease

Finally, select whether the biochemical evidence should be scored, brought up for review by the GCEP, or contradicts the gene-disease association.

Protein interaction evidence should be entered if experimental evidence shows that the gene product interacts with proteins previously implicated in the disease of interest.

The required fields for protein interactions are:

• Experiment name is a free-text field; please choose a descriptive name for the experiment.

• Interacting gene(s) requires entry of a valid HGNC gene name.

• Interaction Type presents a dropdown menu of four options: physical association, genetic interaction, negative genetic interaction, positive genetic interaction.

• Method by which interaction detected presents a dropdown menu of nine different experimental methods.

If the interacting protein has previously been implicated in the disease, check the box next to the corresponding text. Please note that if there is no such evidence, the protein interaction evidence can not be scored.

Finally, select whether the experimental evidence should be scored, brought up for review by the GCEP, or contradicts the gene-disease association.

Curation of expression evidence is based on two options that are selected from a pull-down menu:

• A. The gene is expressed in tissues relevant to the disease of interest.

• B. The gene is altered in expression in patients who have the disease.

The curation interface for both options has a number of required fields, shown with an asterisk next to the field. For both, the required fields are:

• Experiment name is a free-text field; please choose a descriptive name for the experiment.

• Organ or tissue relevant to disease requires an entry in either the Uberon ID or the free text field. Uberon is an integrated cross-species anatomy ontology. A link to Uberon is provided to aid in searching for the correct ID.

If the gene is normally expressed in the tissue implicated in the disease or is altered in patients with the disease, check the box next to the corresponding text. Please note that if no such normal or altered expression has been shown, the gene expression evidence can not be scored.

Finally, select whether the experimental evidence should be scored, brought up for review by the GCEP, or contradicts the gene-disease association.

Model systems evidence shows that a non-human model organism or a cell culture model with a disrupted copy of the gene has a phenotype consistent with the human disease state.

Curation of model systems evidence is based on whether the experiments were conducted with a non-human model organism or a cell culture model; select the appropriate option from the pull-down menu:

The curation interface for both options has a number of required fields, shown with an asterisk next to the field. For both, the required fields are:

• Experiment name is a free-text field; please choose a descriptive name for the experiment.

• Description of gene alteration is a free-text field that enables you to describe how the endogenous gene was altered in the experiment.

• Phenotype(s) observed in model system requires an entry in either the Human Phenotype Ontology (HPO)/Mammalian Phenotype Ontology (MP) ID or the free text field.

• Human phenotype(s) requires an entry in the Human Phenotype Ontology (HPO) ID or the free text field.

• Explanation of how model system phenotype is similar to phenotype observed in humans is a free-text field.

For the "Non-human model organism" option, the additional required field is:

• Non-human model organism presents a dropdown menu of non-human model organism options. New organisms can be added upon request; please email us at clingen-helpdesk@lists.stanford.edu.

For the "Cell culture model" option, the additional required field is:

• Cell culture model type/line requires an entry in either the Experimental Factor Ontology (EFO)/Cell Ontology (CL) ID or the free text field.

Links to the Human Phenotype Ontology (HPO), Cell Ontology (CL) and the Experimental Factor Ontology (EFO) are provided to aid in searching for the correct ID. A link to the Mammalian Phenotype Ontology (MP) is here.

Finally, select whether the experimental evidence should be scored, brought up for review by the GCEP, or contradicts the gene-disease association.

At any time during curation, you can preview your curation progress in two ways. In the Curation Central panel, the "Preview Evidence Scored" button brings up a detailed list of all the currently scored and saved evidence in a new tab. The "View Classification Summary" button brings up the current classification matrix.

Scored Evidence:

The Scored Evidence tables summarize the saved evidence together with the points given (both the default score and the score assigned by the curator). The evidence is sorted according to evidence types (Case Level, Case Level for segregation evidence when there is no associated proband, Case-Control, and Experimental). Evidence with a score status of “Score,” “Review,” or “Contradicts” is shown. Only those rows of evidence where the score status was set as “Score” are included in the calculation for the total points shown at the bottom of each evidence table.

The Scored Evidence tables will be shown in a new tab or window. There is a close button at both the top and the bottom of the page. Be sure to close the tab/window when you are finished, so you do not get confused the next time you generate a Scored Evidence table.

The text within the Label column (the leftmost column) provides a direct link to the curation interface for that evidence. The link will open a new tab where the evidence can be edited. This provides a simple way to correct errors and typos you may find. The table itself does not update automatically based on any corrections you make.

Classification Summary Matrix:

The Classification Summary matrix summarizes all saved evidence and the collated scores. It enables a quick overview and allows you to easily determine whether there is already sufficient evidence to reach the maximum total points in a given evidence category. The points recorded in the "Total Points" column reflect the evidence that has been entered so far; if the number of points exceed the maximum number of points that can be counted towards a classification from a particular evidence type, the "Points Counted" column will show the maximum total points rather than the sum of total points.

In the matrix shown below, the total points collected for variant evidence, 12.4, exceeds the maximum number of points that can be counted; thus, the "Points Counted" column shows only 12 points. The total points collected for genetic evidence overall, 13.5, also exceeds the number of points that can be counted, and thus only a total of 12 points are shown for "Genetic Evidence Total".

Below the Calculated Classification Matrix, a panel containing the summary classification for the Gene-Disease pair enables you to modify (if needed) and save the classification, which will enable moving the gene-disease record to Provisional status.

Evidence Summary:

Upon saving a Classification, you have the option of viewing the summary of the evidence for this Classification by clicking on the “Evidence Summary” button at the bottom of the page. This represents the evidence and any modifications that were just saved and contains both the Calculated Classification Matrix and the Scored Evidence tables.

The Evidence Summary will be shown in a new tab or window. There is a close button at both the top and the bottom of the page. Be sure to close the tab/window when you are finished, so you do not get confused the next time you generate an Evidence Summary.

Printing Summaries

You can print an Evidence Summary by using the "Print PDF" button in the footer following the evidence tables.

Recommended print settings:

• Layout: Landscape

• Scale: 50%

• Margins: Minimum

• Background graphics selected

Rescue evidence shows that the phenotype in humans (i.e. patients with the condition), non-human model organisms, cell culture models, or patient cells can be rescued.

Curation of rescue evidence is based on whether rescue of the phenotype was observed in a human, a non-human model organism, a cell culture model or patient cells; select the appropriate option from the pull-down menu:

The curation interface for all options has a number of required fields, shown with an asterisk next to the field. The required fields are:

• Experiment name is a free-text field; please choose a descriptive name for the experiment.

• Description of gene alteration is a free-text field that enables you to describe how the endogenous gene was altered in the experiment.

• Phenotype to rescue requires an entry in the Human Phenotype Ontology (HPO) ID or the free text field.

• Description of method used to rescue is a free-text field.

For the "Non-human model organism" option, the additional required field is:

• Non-human model organism presents a dropdown menu of non-human model organism options. New organisms can be added upon request; please email us at clingen-helpdesk@lists.stanford.edu.

For the "Cell culture model" option, the additional required field is:

• Cell culture model type/line requires an entry in either the Experimental Factor Ontology (EFO)/Cell Ontology (CL) ID or the free text field.

For the "Patient cells" option, the additional required field is:

• Patient cell type/line requires an entry in the Cell Ontology (CL) ID or the free text field.

Links to the Human Phenotype Ontology (HPO), Cell Ontology (CL) and the Experimental Factor Ontology (EFO) are provided to aid in searching for the correct ID.

Finally, select whether the experimental evidence should be scored, brought up for review by the GCEP, or contradicts the gene-disease association.

Gene-disease curation records move between different states that are indicated by colored labels.

While you are entering evidence, the gene-disease record is shown with an label. When evidence collection is complete and the record is ready for GCEP review, you can save it with a classification label. The Provisional classification will facilitate review of the record by the GCEP by providing summaries of the curated evidence and the associated scores. After the GCEP has discussed the evidence and any requested modifications have been made and saved, the classification can be approved and will then be shown with the classification label.

By saving a Summary or Provisional Classification or approving a classification, you are creating a snapshot of the gene-disease record. You can continue to curate and modify all aspects of the record. However, the snapshot is permanently saved, and its Evidence Summary will be viewable using links in the "Saved Provisional and Approved Classification(s)" section at the bottom of the page when you view the Classification Summary.

Publishing an approved gene-disease record will make it available on the public ClinGen website. It will then appear with the label.

When your saved Approved record is ready to be published, click the Publish Summary button at the bottom of the Classification Summary page:

Clicking the Publish Summary button brings up the "Publish Classification" panel which allows you to select the reason(s) for publication. This information will be used designate the classification's version number on the ClinGen website.

If this is a new curation, please select "New Curation". This disables the other checkboxes as they are only applicable to previously published curations.

If this is a recuration, and/or you are publishing with a minor ("administrative") update, please select all relevant reasons.

After clicking the Preview Publish button above, you will be able to see the information (date, contributor, approver, additional comments etc.) before publishing (note: "Additional comments" are for internal use only and will not be published). Then, clicking the Publish button will publish the record to the ClinGen website.

A Summary Classification can be saved at any time during the curation process. To be able to save, first select the "View Classification Summary" button in the top panel of the gene-disease curation record.

The summary classification panel appears below the Classification Matrix and allows you to save the current clinical validity classification. In the panel, you can also select whether the evidence for a strong classification has been replicated over time (required for a "Definitive" classification). A free-text evidence summary must be provided before saving.

By default, the Clinical Validity Classification value calculated from the scored evidence will be saved. This value can be manually modified; to do so, select the chosen clinical validity term from the drop-down menu. If a modification is made, an explanation in the "Explain Reason(s) for Change" field is required.

A free-text summary of the gene curation evidence must be entered in the “Evidence Summary” box; this summary will be displayed on the website when the final clinical validity classification is published. Specific guidance and a sample Evidence Summary text is provided here. The Evidence Summary text can be entered and formatted using the edit tool on the left hand side, and the right hand side panel will automatically show how the formatted text will be displayed on the website when it is published.

Clicking the “Save” button at the bottom of the Calculated Classification Matrix box will save the Classification.

Upon saving, the contents of the panel will be updated to reflect the saved options, including a time stamp for the saving operation. Buttons that link back to the Record Curation page (Curation Central), to re-edit the Summary Classification, or to view the current Evidence Summary (which opens in a new tab or window) are provided.

With every visit to the "View Classification Summary" page, the three editable fields in the panel are available to be edited and saved again (i.e. you may update the modification based on any new Calculated Classification, update the "Reason(s) for Change" text, and/or update the evidence summary text).

If the final classification of a GDM is "No Known Disease Relationship", the calculated classification was not modified, and only animal models were counted towards the experimental evidence, an "Animal Model Only" tag is displayed.

Functional alteration evidence shows that cultured cells in which the function of the gene has been disrupted have a phenotype that is consistent with the human disease process.

Curation of functional alteration evidence is based on whether the experiments were conducted with Patient cells or Non-patient cells; select the appropriate option from the pull-down menu:

The curation interface for both options has a number of required fields, shown with an asterisk next to the field. For both, the required fields are:

• Experiment name is a free-text field; please choose a descriptive name for the experiment.

• Normal function of gene/gene product requires an entry in either the Gene Ontology (GO) ID or the free text field.

• Description of gene alteration is a free-text field that enables you to describe how the function of the gene was altered in the experiment.

• Evidence for altered function is a free-text field that enables you to describe the evidence presented in the publication.

For the "Patient cells" option, the additional required field is:

• Patient cell type requires an entry in either the Cell Ontology (CL) ID or the free text field.

For the "Non-patient cells" option, the additional required field is:

• Non-patient cell type requires an entry in either the Experimental Factor Ontology (EFO)/Cell Ontology (CL) ID or the free text field.

Links to the Cell Ontology (CL) and the Experimental Factor Ontology (EFO) are provided to aid in searching for the correct ID.

Finally, select whether the experimental evidence should be scored, brought up for review by the GCEP, or contradicts the gene-disease association.

Disease terms cannot be changed on published gene-disease records so it must be unpublished first. Select the "Unpublish Summary" link in the "Saved Provisional and Approved Classification(s)" panel.

A new panel will appear above the "Saved Provisional and Approved Classification(s)" panel

You can now return to Curation Central for the gene-disease record, and the "Disease" edit button in the header will be active and allow you to select a new disease term.

After you've selected a new disease term and are ready to republish the classification, select "Administrative Update: Disease Name Update."

The Standard Operating Procedure (SOP) for Gene-Disease Validity recuration is located here.

The GCI API currently allows user queries producing three different reports:

• Affiliations List

• GCI Summary Report

• GCI Probands Report

To be able to use the GCI API, you will need an API Key. Access to the API is limited to GCEPs. Please contact the GCEP coordinator to receive an API Key. You will also be provided with the correct URL to use.

Affiliations List

The Affiliations List returns the following information about all affiliations in JSON format:

• affiliation_id - the five-digit identifier for an affiliation, e.g. "10007"

• affiliation_fullname - the full name of the affiliation, e.g. "Hearing Loss"

• publish_approval - if approval is required, this returns "true"

• subgroups:

  • gcep

    • id - the five-digit identifier for the affiliated GCEP, e.g. "40007"

    • fullname - the full name of the GCEP, e.g. "Hearing Loss GCEP"

  • vcep

    • id - the five-digit identifier for the affiliated VCEP, e.g. "50007"

    • fullname - the full name of the VCEP, e.g. "Hearing Loss VCEP"

    • guidelines_name - the name of this VCEP's guidelines, e.g. "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1"

    • guidelines_url - the URL where the guidelines can be accessed, e.g. "https://www.clinicalgenome.org/affiliation/50007/docs/assertion-criteria"

• approver - the list of official approvers, e.g.

  • 0: "Jane Doe"

  • 1: "John Smith"

How to use the API

The following input variables are required:

• API_Key: replace API_Key with your API Key

• URL: replace URL with the proper URL

• name for the output file

Example: curl -H "x-api-key:API_Key" -G "URL/affiliations?target=api" >FileName.json will return the list of ClinGen affiliations to a file named FileName.json.

GCI Summary Report

The GCI Summary Report returns the following information about each GDM curated in a specific GCEP in JSON or comma-separated value (csv) format:

• Gene: e.g. "KCNQ2"

• Disease: e.g. "undetermined early-onset epileptic encephalopathy"

• Mode of Inheritance: e.g. "Autosomal dominant inheritance (HP:0000006)"

• GCEP Affiliation: e.g. "Epilepsy GCEP"

• SOP Version: e.g. "5"

• Final Classification: e.g. "Definitive"

• Final Classification Date: e.g. "2018-06-14T14:53:52.571Z"

• Genetic Total Points: e.g. 12

• Experimental Total Points: e.g. 4

• Total Points: e.g. 16

• Proband Count: e.g. 14

• Scored Proband Count: e.g. 14

• Earliest PMID Year: e.g. "2012"

• Most Recent PMID Year: e.g. "2013"

• GDM UUID: e.g. "f33b00b8-81c5-4fa5-af66-2ca43b3b4995"

How to use the API

The following input variables are required:

• API_Key: replace API_Key with your API Key

• URL: replace URL with the proper URL

• curation status: status=published or status=approved

• time window during with the GDM was published or approved:

  • start=yyyy-mm-dd

  • end=yyyy-mm-dd

• affiliation id: use the five-digit identifier, e.g. affiliation=10005

• optional output format as csv file: -d format=csv

• name for the output file, e.g. FileName.json or FileName.csv

Example: curl -H "x-api-key:API_Key" -G "URL/snapshots" -d target=gci -d name=summary -d status=published -d start=2017-01-01 -d end=2021-09-28 -d affiliation=10005 -d format=csv >10005.csv will return the summary report for the 10005 affiliation for gene-disease records published between 1/1/2017 and 9/28/2021 to a file 10005.csv.

Alternatively, you can choose to print a count of the GDMs to the command line (i.e. no file output) using -d count:

Example: curl -H "x-api-key:API_Key" -G "URL/snapshots" -d target=gci -d name=summary -d status=published -d start=2017-01-01 -d end=2021-09-28 -d affiliation=10005 -d count will produce an output in the terminal: {"Number of curation found": "106"}

GCI Probands Report

The GCI Probands Report returns detailed information about all probands for a specific affiliation. Probands are listed by the GDM record; the output follows this format:

• Gene: e.g. "KCNQ2"

• Disease: e.g. "childhood-onset epilepsy syndrome"

• Mode of Inheritance: e.g. "Autosomal dominant inheritance (HP:0000006)"

• Status: e.g. "approved"

• Approval Date: e.g. "2021-01-25T15:10:06.266Z"

• Approval Review Date: e.g. "2017-10-20T16:00:00.000Z"

• Probands: information about each proband is listed in their own numbered section, e.g.:

  • score

    • Variant Type: e.g. "Variant is de novo"

    • Score Status: e.g. "Supports"

  • variants: list of variants associated with the proband, e.g. "NM_020822.3(KCNT1):c.2800G>A (p.Ala934Thr)"

  • label: e.g. "Male 1"

  • HPO terms: list of HPO terms, e.g. "HP:0011153" "HP:0001290"

  • HPO terms text: e.g. "Focal, generalized, and tonic seizures once per day. [...]"

  • Zygosity: e.g. "Homozygous"

  • Previous Testing Description: e.g. ""negative for SCN1A mutations. De novo mutations [...]"

  • Genotyping Methods: list of methods, e.g. "Exome sequencing"

  • PMID: e.g. "23086397"

How to use the API

The following input variables are required:

• API_Key: replace API_Key with your API Key

• URL: replace URL with the proper URL

• curation status: status=published or status=approved

• time window during with the GDM was published or approved:

  • start=yyyy-mm-dd e.g. start=2021-01-25

  • end=yyyy-mm-dd

• affiliation id: use the five-digit identifier, e.g. affiliation=10005

• name for the output file, e.g. FileName.json

Example: curl -H "x-api-key:API_Key" -G "URL/snapshots" -d target=gci -d status=approved -d start=2021-01-25 -d end=2021-07-28 -d affiliation=10007 >10007.json will return proband data from approved gene-disease records approved between 1/25/2021 and 7/28/2021 for the 10007 affililation to a file named 10007.json.

Alternatively, you can choose to print a count of the GDMs to the command line (i.e. no file output) using -d count:

Example: curl -H "x-api-key:API_Key" -G "URL/snapshots" -d target=gci -d status=approved -d start=2021-01-25 -d end=2021-07-28 -d affiliation=10007 -d count will produce an output in the terminal: {"Number of curation found": "7"}

When curation of a record is complete and ready for review by the expert panel, it can be moved to Provisional status.

Below the saved Summary Classification panel (see previous step), a new option enables you to save the curation and Summary Classification as a Provisional record. You can enter the date the curation was reviewed by you prior to saving, and add any additional comments in a free-text field.

When you are ready to save the gene-disease curation as Provisional, select the "Preview Provisional" button.

The preview will show the timestamp of the submission, which is equivalent to the time at which the Provisional Classification is saved. Select the "Submit Provisional" button when you are ready.

After submitting/saving a Provisional classification, a panel providing the option to approve the gene-disease record will appear (see following section). The panel below that summarizes the saved classifications for the gene-disease record. Selecting the "Provisional Summary" link will open a new page or tab that shows the current Evidence Summary for the saved classification.

The top panel of the Evidence Summary shows top-level information about the gene-disease record and is followed by a panel containing the free-text curation summary (also labeled "Evidence Summary").

This is followed by the Calculated Classification Matrix and Scored Evidence tables. As in the preview version (see the description here), the tables summarize the saved evidence, sorting it according to evidence types (Case Level, Case Level for segregation evidence when there is no associated proband, Case-Control, and Experimental). Evidence with a score status of “Score,” “Review,” or “Contradicts” is shown. Only those rows of evidence where the score status was set as “Score” are included in the calculation for the total points shown at the bottom of each evidence table.and a series of tables

Below the Curation Central header panel, the central panel will now show the Provisional classification. It also now gives you the option to "View/Approve Current Provisional".

The Human Phenotype Ontology (HPO) provides a standardized vocabulary of phenotypic abnormalities encountered in human disease. https://hpo.jax.org/app/

Using HPO Search

Use the drop-down list to limit search to Term (phenotype), Disease, Gene, or search All.

• Enter a phenotype to find its HPO number

• Enter a disease to find associated gene(s) and phenotypic features

• Enter a gene to find associated disease(s) and phenotypic features

The HPO search tool has a type-ahead function. Below is an example of what is found after typing "spre" when searching All:

Up to 10 items of each type will be displayed. If the desired term is shown, click on it to go directly to its entry. If it is not listed, click on the blue "See all results for" button, or hit Enter/Return to be taken to a search results page.

The page for each phenotypic term includes a hierarchy of related terms. From here, you can select a broader and narrower term if appropriate.

Once a term has been selected, the HP number can be copied from the title line and then pasted into the curation interface.

Return to Curation Help

After the expert panel has met and voted to approve the gene-disease record, the provisional record can be approved in the GCI.

When your saved Provisional record is ready to be approved, either select the "View/Approve Current Provisional" button in the "My classification" section of the Curation Central page:

or select the "Approve" button at the bottom of the Classification Summary page:

Both options will bring up a new panel. If you need to acknowledge other contributors (e.g. other GCEPs), select the button, which will expand the section of the panel and enables you to enter additional contributors. Guidance on acknowledging other contributors can be found in Appendix D of the SOP.

To approve a classification, you must enter the final approval date. This should be the date on which the GCEP has voted to approve the gene-disease classification and can predate the date the approval is saved in the GCI. If curation was performed using criteria from an older version of the SOP, you can select it from the drop-down menu. The current version is shown by default.

Once you select "Preview Approval," you will be able to see the information (date, approver, additional comments etc.) for the Approval. Selecting "Submit Approval" will save the record as "Approved".

After submitting/saving the approval, a panel providing the option to publish the gene-disease record will appear (see following section). The "Saved Provisional and Approved Classification(s)" panel below shows all saved classifications for the gene-disease record; the newly approved classification will be marked with a green flag indicating that it is the most current approved record. Selecting the "Approved Summary" link will open a new page or tab that shows the current Evidence Summary for the saved classification.

Below the Curation Central header panel, the central panel will now show the Approved classification; the "View Current Approved" button opens a new window or tab with the approved Evidence Summary.

Wherever possible the VCI and GCI ensures rigorous and standardized data capture of specific evidence types by the use of ontologies and controlled vocabularies (examples shown in table below).

Most ontologies can be searched using the EMBL-EBI Ontology Lookup Service. We provide detailed guidance on how to look up MONDO disease terms and HPO phenotypes.

1. Click the “View Classification Summary” button in the GCI:

1. Click the "Edit Published Summary" button:

1. Make select edits in the "Edit Published Summary" selection panel that opens after clicking the "Edit Published Summary" button:

Fields that can be edited are in white:

• Approval Review Date

• Secondary Contributor(s)

• Secondary Approver

• Evidence Summary (click on the pencil icon to edit evidence summary text)

Fields cannot be edited are greyed out:

• Date Initially Published

• New Publish Date (this auto-updates upon saving)

• Curation Reason (admin updates are only permissible curation reason)

• Publish Submitter name (this auto-updates upon saving)

Note: Users must check the confirmation box in order to save and re-publish their edits to the ClinGen website.

Clicking the Save & Republish button saves and re-publishes the summary and closes the modal and returns the user to the prior page, now updated:

1. After clicking the Save & Republish button, the Approved Section retains the following:

• Name of the original submitter who entered the classification

• Original date saved as approved

After clicking the Save & Republish button, the Published Section shows the following:

• Name of the person who edited the published summary

• The date/time of their edits were saved and republished

• If more than one edit has been made in the history of the record, the name of the most recent editor is displayed

• The curation reason will always be Administrative Update: Error and/or Clarification

5. To view all prior edits:

• Click on the "View Published Edits History" link

• This will take you to a new tab with a side by side comparison of the current Published Summary and its previous version.

The new tab that opens after clicking the View Published Edits History link includes a before/after comparison of the Published Summary. Before fields (left) are in grey, after fields (right) are in blue. History is sorted in reverse order, with most recent edits at the top of the tab. Any text that was removed from the prior evidence summary is highlighted in red on the before side of the Published Summary. Any text added to the re-published evidence summary is highlighted in green on the after side of the Published Summary.

Note: before and after contents of other fields in Published Summary are not highlighted, but are viewable (contributor, approver, etc)

In the event that text gets replaced between publish events, both before and after evidence summaries will highlight the impacted text (e.g., punctuation, capitalization or word changes).

This before/after view is available for every edit made to the Published Summary.

Changes to the published summary will result in minor incremental version changes to the curation record, and will be published to the website.

Upon registration as a user of the ClinGen Variant Curation Interface (VCI), I acknowledge and agree to the following terms:

1. Any data entered into the VCI may be made publicly accessible, either through the VCI directly or by subsequent transfer to other public resources (ClinVar, ClinGen Evidence Repository, etc.);

2. All unpublished patient-specific data entered into the VCI, which is not explicitly consented for public sharing, should be the minimum necessary to inform the clinical significance of genetic variants;

3. Data entered into the VCI should not include or equivalent identifiable information as defined by regulations in your country or region;

4. Data accessed through the VCI should not be used in a manner that is likely to compromise the privacy of individuals. Users agree that they will not attempt in any way to identify or re-identify data subjects;

5. Users understand that they may be personally identified on the basis of information provided during registration, including (but not limited to) names, email addresses, professional affiliations, and curation activities in the VCI.

For information about the publication of data in the ClinGen curation ecosystem, data sharing, and informed consent in clinical genomics in the United States, please consult the ClinGen Terms of Use (), ClinGen Broad Data Sharing Consent Resources (), the NHGRI Policy on informed consent () and this "Points to Consider" regarding data sharing in public databases:

Clinical Genome Resource (ClinGen)

The National Human Genome Research Institute (NHGRI) established the Consortium in 2013 to fill a gap of organized, available information about which genes and genomic variants are relevant to human disease. The Consortium works to identify which genes are associated with disease (through a process known as gene curation) and which variants in those genes are disease-causing (via variant curation). Then, they work to standardize the way researchers document and share information about those variants.

Stanford ClinGen

The primary work of the Stanford ClinGen team focuses on the development of software infrastructure to support the gene-disease curation and variant curation processes that provide the curated information to build ClinGen’s publicly available knowledgebase.

Two such pieces of essential software include: the Variant Curation Interface (VCI), which supports the FDA-recognized ClinGen process, and the Gene Curation Interface (GCI), which supports gene-disease curation following ClinGen’s framework. The VCI and GCI enable curators to associate pertinent evidence with variant interpretations and gene-disease associations, to assess evidence per variant and gene curation protocols, to support expert review of the curated data, and to make their assertions publicly available so that they can be used by anyone seeking to improve patient care through genomic medicine. The VCI is a community curation tool, and so all interested variant curators are encouraged to to use it.

Allowed ontology (MONDO IDs)

merges several different vocabularies into a single ontology structure, including some non-human disease ontologies. These include , , , , and others.

The interfaces support the entry of MONDO IDs, which may be mapped to one or more different ontologies such as those listed above.

Finding a MONDO term

Use the to find the correct disease term (this search is linked from the disease selection screen in the ClinGen interfaces). Note: be certain you are only searching MONDO in the OLS as it supports the search of a wide variety of ontologies:

Using MONDO search

The MONDO OLS has a type-ahead function. Below is an example of what is found after typing “preimpla”

If you select a term from the first list or use the search button, you will be taken to a search results page with filtering options.

If you "jump to" a term with a MONDO ID, you will be taken directly to the page for that ID.

Return to the curation interface paste the MONDO ID into the "Add Disease" selection screen:

Return to Curation Help

Selecting a Variant

Variant information is added while entering different types of evidence into the GCI. The interface accepts ClinVar Variation IDs (numerical), ClinGen Allele Registry IDs ("CA" followed by digits) and ClinGen Allele Registry Copy Nunber IDs ("CACN" followed by digits) as input.

Clicking the "Retrieve" button loads information on the specific variant you selected. Click "Save" if the variant is correct.

Scoring Variants

• Variant Type is a dropdown menu; select from Predicted or Proven Null, Other Variant Type.

• Is this variant is de novo? is a dropdown menu with Yes/No options; if you answer "yes", you also must select whether the maternity and paternity of the variant has been confirmed.

• Is there functional data to support this variant? is a dropdown menu with Yes/No options.

Based on the answers to these questions, a default score for the variant is assigned and shown in the interface. You can override the default score, but must provide an explanation if you do. Both the score and explanation will appear here and in the Scored Evidence table.

In the above example, only one variant is shown. If a second variant is added it will appear on a second row of the table, and the totals for both variant scores will be summed (up to score limits, see SOP).

If Homozygous is selected, there is no requirement to enter a second variant. The first variant entered will be automatically entered twice into the scoring table.

Phase Status

As of August 2024, scoring probands for AR conditions now requires specification of phase status. When entering biallelic variants into the GCI, the curator will have to check a box to attest if variants are either:

• Homozygous

OR

• Proven or suspected in trans

"Proven in trans" means each parent confirmed heterozygous, or the two variants are close enough to each other to discern phase from sequence data. "Suspected in trans" is intended for situations where data from both parents may be unavailable, but the proband's phase can be inferred based on one parent’s genotype and/or certain sibling genotypes.

Once you confirm that the two variants are proven or suspected in trans, there will be a second set of checkboxes where you can choose if the variants are:

• Proven in trans

• Suspected in trans

• Phase unknown.

If curator selects phase = proven in trans or suspected in trans, two variant names must be provided to score the evidence. Once two variants in trans are entered and scored as outlined in the above Scoring Variants section, then the record can be saved.

"Phase Unknown" means that proband phase cannot be inferred, as no genotypes are provided aside from the proband’s. If “phase unknown” is selected, you can still enter the variants observed and save them, but there will be no option to score them.

Note: Because phase unknown variants are not being scored, they will not appear in the preview evidence scored tab nor in the classification summary’s scoring matrix. Therefore, in cases where the phase of the variants is entirely unknown, the curator is encouraged to mark phase unknown observations in the non-scorable evidence section on the curation panel in the GCI landing page (e.g. “curation central”) under the relevant PMID. Similarly, observations where only a single variant is observed, but a second variant is suspected despite note being reported, use non-scoreable evidence section for such observations.

Once two variants are entered and scored, the record can be saved. Note that phasing of up to two variants is supported for AR and semidominant gene-disease modes of inheritance at this time. Phasing for >2 variants is not currently supported.

The top section of the curation interface shows the publication currently being curated.

Case-control studies are those in which statistical analysis is used to evaluate enrichment of variants in cases compared to controls. Each case-control study should be independently assessed based on the criteria outlined in the SOP (Case-Control Data section) to evaluate the quality of the study design. The score status of case-control studies can now also be selected as "Review" or "Contradicts".

All required fields (marked with a star) must be filled in before the curated record for an individual can be saved. The required fields are:

• Case-Control Label, Case Cohort Label and Control Cohort Label are free-text identifiers assigned by the curator. They should be used to uniquely identify the cohorts described in a publication. If possible, use the identifiers given in the publication.

• Disease(s) in Common -- usually select “Copy disease term from Gene-Disease Record”.

• Number of Cases with variant(s) in the gene in question -- fill in the number given in the publication

• Number of Controls with variant(s) in the gene in question -- fill in the number given in the publication

• Number of all Cases genotyped/sequenced -- fill in the number given in the publication

• Number of all Controls genotyped/sequenced -- fill in the number given in the publication

For the sections sections following the Case-Control Label, there is a split screen where Case Cohort information is entered in the left panel and Control Cohort information is entered in the right panel.

In the case cohort "Disease(s) & Phenotype(s)" section, you must enter either disease or phenotype information. Generally, you can simply copy the disease from the gene-disease record. In the "Demographics" and "Methods" subsections, enter as much information as is given in the publication.

Additional required information for both cases and controls must be entered in the "Power" section. Additional information can be entered for both cases and controls in the "Additional Information" section below.

The "Case-Control Evaluation" section enables you to enter information that is used by the GCEP to determine whether the study can be scored. A "Study type" must be entered in order to score the study. The following "Statistics", "Bias Category" and "Comments" subsections facilitate evaluation of the quality of the case-control study.

Case-control studies are evaluated and points are assigned at the discretion of experts. The "Case-Control Score" section now allows the selection of a scoring status that includes the "Review" and "Contradicts" options. To score a study, select "Score" and the appropriate numerical value from the "Score" drop-down menu.

General Information

Account Information and Login Troubleshooting

Affiliations

Other Troubleshooting

Who should I contact for further help?

If you run into other issues with the VCI or GCI, please contact our helpdesk at clingen-helpdesk@lists.stanford.edu.

For issues with or questions on other interfaces and tools, please see ClinGen Resources for a list of who to contact regarding particular concerns.

VCI and GCI

If you have questions about the VCI/GCI or experience technical difficulties, please email the helpdesk at clingen-helpdesk@lists.stanford.edu.

Variant Curation

For training, SOP and additional resources, visit Variant Pathogenicity Training Materials.

If you have questions about variant curation, contact the Variant Curation Working Group at variantcuration@clinicalgenome.org.

Gene-Disease Curation

For training, SOP and additional resources, visit Gene-Disease Clinical Validity Training Materials.

If you have questions about gene-disease curation, contact the Gene Curation Working Group at genecuration@clinicalgenome.org.

Other ClinGen Tools

General Questions

For all other questions, contact clingen@clinicalgenome.org

The Stanford ClinGen team is housed in the and overseen by Co-Principal Investigator .

The team shares one of the NIH ClinGen awards with Baylor College of Medicine under Co-PIs , and .

Leadership

, Principal Investigator, ClinGen, PharmGKB, CPIC, and PharmCAT

, Co-Principal Investigator, ClinGen

, Director, PharmGKB

Product Managers/Coordinators

Software Developers

Gloria Cheung

Mark Mandell

Liam Mulhall

Gabriella Sanchez

Ryan Whaley

Bryan Wulf