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

If you have an account and are unable to log in, see

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

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 "[email protected]" is NOT the same as "[email protected]"

If you still need assistance, email us at .

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:

In the Affiliation Bar, click to open the Select Affiliation screen.

Select the desired Affiliation (or no Affiliation) from the dropdown menu and click

From within the VCI or GCI:

In the Affiliation Bar, click to return to the Dashboard and then click

Affiliation Management

Setting up an Affiliation

ClinGen expert panels will have an affiliation set up in the interfaces after Step 1 approval. We also support non-ClinGen affiliations in the VCI for any group who wish to curate together. To request a new affiliation, please email the helpdesk at , and provide the following information:

• 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

To request updates, such as adding/removing remembers or changing the Affiliation name, the Coordinator should email the helpdesk at .

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.

Retrieve the code from your email and use that to authenticate your email address. You will also be asked to agree to the site's .

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

• For the production site you must be validated by an admin to finalize access. This may take a few days and you will be emailed when it's completed. Email us at to expedite the process.

• If you are a part of a curation affiliation, please follow the above steps and also ask your coordinator to arrange for you to be added to the affiliation. The ClinGen Variant Curation Interface is available for public use. The ClinGen Gene Curation Interface is restricted to use by ClinGen curators. If you would like to collaborate on gene curation, please contact ClinGen at

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.

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.

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.

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.

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 .

Begin variant curation

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

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.

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:

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.

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

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.

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 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)

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.

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

It has recently come to our attention that the National Library of Medicine has been piloting 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.

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.

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.

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

Approval Process Workflow

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.

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)

• • Available to users curating as part of any affiliation

  • Process is manual (data is downloaded to spreadsheet)

Both publishing options are available via the Summary Page.

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.

Clinical Genome Resource (ClinGen)

The National Human Genome Research Institute (NHGRI) established the Clinical Genome (ClinGen) Resource 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.

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

In the new selection screen, you can enter a disease name in free text (up to 100 characters in length). Please remember that if someone else enters a different name for the same disease, the interface will not be able to determine that they are equivalent. You must also provide either a set of Human Phenotype Ontology (HPO) terms (preferred -- a link to the is provided; see also ) or a free-text definition for the term you are entering. You may also provide both. Click "Save" to save the new disease record.

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.

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.

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.

After saving, you will see the associated disease listed under the variant, as well as under "My Interpretation" and the Disease+ button will be replaced with

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 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 terms (preferred) and/or a definition for the term you are entering.

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.

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.

C. Click to add a specification document to the curation

D. Click or "Add Disease +" under "My Interpretation" to associate a disease with the variant.

E. Click to add mode of inheritance.

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 evaluations where you can indicate whether an individual criterion is “Met” (see ).

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 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.

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

Case/Segregation Tab Organization

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 (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

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 is the accession in 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, 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.

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 . Approved variant interpretations are published to the and to .

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

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

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

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 () includes Curated Evidence

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:

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

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

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

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.

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.

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.

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.

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)

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:

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

An label will now appear in the "Saved Provisional and Approved Classification(s)" panel.

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)

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

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.

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 "Add" button will change to a "Remove" button

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."

Allowed ontology (MONDO IDs)

MONDO (Monarch Disease Ontology) merges several different vocabularies into a single ontology structure, including some non-human disease ontologies. These include Orphanet, OMIM, Disease Ontology (DO), NCIt, EFO 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.

If the term is correct, copy the “ID” (“MONDO:0000218” in this example). You can click Copy in the OLS header to save the MONDO ID for that entry to your clipboard.

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

Return to Curation Help

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 .

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.

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:

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.

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

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.

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 )

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.

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.

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.

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:

Access the variant prioritization tool

Initiate a new variant curation

Initiate a new gene curation; disabled (grayed out) if not logged in to a ClinGen GCEP affiliation

Return to the dashboard

Access help resources. Pulldown menu options include links to this documentation, GCI and VCI SOPs, Terms of Use/User Agreement, GeneTracker tool (requires separate login), and email helpdesk.

Log out of the interface

Affiliation Bar

Available from all pages. Displays current affiliation. Click to change the affiliation you are curating under.

Header

Displays the account and affiliation you are logged in under.

Tool Bar

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

All Variant Interpretations – This list contains all Interpretations curated to date, by all users/affiliations, along with disease/mode of inheritance, and date created.

My Variant and Gene Interpretations - These tables list all VCI and GCI entries for the user or logged-in affiliation.

All Gene-Disease Records – This list contains all the Gene-Disease Records curated to date, by all users/affiliations, along with disease/mode of inheritance, and date created.

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

Begin Curation

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

For assistance with the GCI, go to:

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 .

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:

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

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 and are as follows:

1. Benign

2. Likely benign

3. Uncertain significance

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

A new panel allows you to enter information on the selected variant; for guidance, please see the Variant Evidence section. There a a few questions that must be answered in order to score each variant. The required fields are:

• 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.

Once the required data has been entered, you will be able to select the scoring status of the variant, i.e. whether the variant in the proband should be scored, whether the proband and variant should be flagged for review by the GCEP, or whether the evidence from this variant contradicts the gene-disease relationship. Guidance on variant scoring can be found in the Variant Evidence section.

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.

Population data in the GCI

For proband variants added to the GCI after January 2026, the GCI will pull gnomAD version 4.1 data sourced from ClinGen’s for direct display in the GCI.

For variants added to the system before January 2026, users will need to prompt the GCI to fetch the gnomAD frequency data if desired. Users can select the “Retrieve gnomAD data” button from the individual > variant view in the GCI to fetch and display the gnomAD GroupMax Filtering Allele Frequency data.

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 new calculated Total Points now suggest a Calculated Classification that is the same as a modified classification saved on the last visit, the modified classification will be reset to “No Modification”, and a red warning message will be displayed to explain this. If the Summary Classification has been saved previously, the tag will appear in the "My classification" section of the GDM dashboard.

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.

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.

A. Click to make further edits to the Evaluation Summary

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

F. Click to initiate the process for Provisionally Saving the Interpretation

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 and GCI

If you have questions about the VCI/GCI or experience technical difficulties, please email the helpdesk at .

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.

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.

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.

General Information

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Affiliations

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