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GCI Curation Help

Christine Preston edited this page Jul 15, 2019 · 107 revisions

Gene Curation Interface Help Doc

Table of Contents

OVERVIEW OF CURATION

  1. Quick Reference Guide
  2. Curator Workflow

REGISTRATION

  1. When to Register
  2. How to Register

LOGGING IN

  1. Demo Login
  2. ClinGen Registered User Login
  3. Google Login
  4. Login Troubleshooting

AFFILIATIONS

  1. What is an Affiliation?
  2. Select Affiliation
  3. Change Affiliation
  4. Affiliation Management

GENERAL NAVIGATION

  1. Dashboard View

CREATING A GENE DISEASE RECORD

  1. Identifying the Gene
  2. Identifying the Disease
  3. Identifying the Mode of Inheritance
  4. Free text option for disease
  5. Selecting an Adjective (optional)

STARTING CURATION

  1. Curation Central View
  2. Adding a PubMed article to the Gene-Disease Record

ADDING GENETIC EVIDENCE

  1. Curate Group Information
  2. Curate Family Information
  3. Curate Individual Information
  4. Curate Case Control Information

ADDING EXPERIMENTAL EVIDENCE

  1. Curate Experimental Information

CLASSIFICATION MATRIX

  1. Viewing the Classification Matrix
  2. Classification Matrix Features

SAVING & MODIFYING A SUMMARY CLASSIFICATION

  1. Modifying a Classification
  2. Saving a Summary Classification
  3. Revisiting the Classification Matrix

EVIDENCE SUMMARY

  1. Evidence Summary Header
  2. Evidence Summary Tables
  3. Printing Evidence Summary & Saving as PDF

SAVING AS PROVISIONAL AND APPROVED

  1. What do Provisional and Approved mean?
  2. Saving as Provisional
  3. Saving as Approved
  4. Creating New Provisional and Approved Classifications

PUBLISHING APPROVED CLASSIFICATIONS TO THE CLINGEN WEBSITE

  1. Before Publishing
  2. Who Can Publish?
  3. How to Publish
  4. How to Unpublish

OVERVIEW OF CURATION

1. Quick reference guide

Quick reference guide

2. Curator Workflow

Workflow

REGISTRATION

1. When to Register

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

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

2. How to Register

i. If you are a ClinGen curator, you may request an account by emailing us at clingen-helpdesk@lists.stanford.edu. The ClinGen Variant Curation Interface is available for public use. However, the ClinGen Gene Curation Interface is currently restricted to use by ClinGen curators. If you would like to collaborate on gene curation, please contact ClinGen at clingen@clinicalgenome.org.

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

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

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

c. Any affiliation you have with ClinGen

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

LOGGING IN

1. Demo Login

You can try out the test/demo version of the ClinGen interfaces (https://curation-test.clinicalgenome.org/) by simply clicking on the 'Demo Login' button in the header.

You will be logged in to the test version of the interfaces under a generic “ClinGen Curator” account.

2. 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 with us can login by clicking the “Login” button in the header. The Auth0 authentication system will now produce a pop-up login window.

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

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

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

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

3. Google Login

You will note that one of the options on the login window is “LOG-IN WITH GOOGLE.”

You can click this button and log in with a Google email account, however this option is only available for Google emails that have been registered as the preferred email address by a ClinGen curator. You would need to contact us if you wish to change your preferred email to a Google email address.

4. Login Troubleshooting

i. Have you registered your email address by emailing us at clingen-helpdesk@lists.stanford.edu? ii. Have you received confirmation from us that your email address has been registered?

AFFILIATIONS

1. What is an Affiliation?

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

  1. Edit and score/evaluate same piece of evidence
  2. Work on same classification/interpretation
  3. Approve the same classification/interpretation

2. Select Affiliation

If a user is not part of any Affiliations then there will be no difference from their current workflow. All actions they take in the interfaces will be attributed to them alone.

If a user is as a member of at least one Affiliation, then after logging in they will be presented with a modal.

Within the pulldown the user can choose to select 'No Affiliation (User Name)', in which case they can continue to the interfaces with no difference from their current workflow, or they can select one of the Affiliations they are a member of from the list and all actions taken within the interfaces will be attributed to the selected Affiliation.

Once an Affiliation has been selected then a dark blue Affiliation banner will appear beneath the header, which will show the Affiliation name. This Affiliation banner will be present on every page during the session.

3. Change Affiliation

On the dashboard page a user can change Affiliation at any time by clicking on the 'Change Affiliation' button in the Affiliation banner. The Affiliation pop-up modal will re-appear and a new Affiliation can be selected from the pulldown.

On other pages within the interfaces there is a helpful 'home' button link within the Affiliation banner that will take you back to the dashboard. Once back on the dashboard page, a user can change Affiliation by clicking on the 'Change Affiliation' button in the Affiliation banner and proceed as above.

4. Affiliation Management

i. Setting up an Affiliation

To request to set up a new Affiliation the Coordinator should email the help-desk at clingen-helpdesk@lists.stanford.edu, and provide the following information:

  • Name of the Affiliation
  • Name of the Coordinator
  • Email address of the Coordinator
  • Names of all members of the Affiliation
  • Email addresses of all members of the Affiliation (these should be the email addresses used in their interface registration)
  • Names of the Approver(s) for the Affiliation (if no Approver(s) are selected then by default all Approvals will be by the Affiliation with no Approver shown)
  • Email addresses of the Approver(s)
  • Whether the Affiliation will need to submit Interpretations/Classifications to the ClinGen website (clinicalgenome.org)

ii. Managing an Affiliation

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

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

iii. Updating an Affiliation

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

GENERAL NAVIGATION

1. Dashboard view

a Dashboard home – available from all pages

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

c Navigating to “Create Gene-Disease Record” (described below) – available from all pages d Navigating to the online Help documentation – available from all pages

e Navigating to “Select Variant for Variant Curation”

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

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

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

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

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

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

m. Logout – available from all pages

CREATING A GENE DISEASE RECORD

NOTE: Currently, once a Gene:Disease Record has been created, the disease can be altered up until a PMID has been added. However, the gene, mode of inheritance, and adjective cannot be altered after the record has been created. Please be certain you have selected the desired fields correctly from the beginning.

1. Identifying the Gene

A curator is required to identify the specific gene by entering an approved HGNC gene symbol. A link out to HGNC is provided for a curator to look up the correct symbol for their gene.

2. Identifying the Disease

A curator is required to identify the specific disease by entering an MonDO ID. Click on the “Disease +” button to add a disease For additional help in searching for MonDO IDs, please see the “MonDO Search Help” link (https://curation.clinicalgenome.org/static/help/MonDO-search-help.pdf) for further instructions.

After entering an ID and selecting “Retrieve from OLS,” the term name and definition (if one exists) will be returned. Select “Save” if this is the desired term.

After entering an ID and saving, the disease term name, ID, and definition (if one exists) will be displayed on the Create GDM page:

3. Identifying the Mode of Inheritance

A curator is required to identify the specific Mode of Inheritance by choosing from the selection available in the pull-down.

4. Free text option for disease

If there is no MonDO term, a free text term may be entered for the disease. Note: using a disease identifier if highly recommended. If you cannot find an appropriate one, please feel free to contact us at clingen-helpdesk@lists.stanford.edu and we will be happy to assist.

To enter a free text term, verify you click on the checkbox (see arrow below)

This will take you to a page where you can enter a free text term (up to 100 characters in length). You must also provide either a set of HPO terms (preferred) or a Definition for the term you are entering. You may also provide both. Please remember that if someone else enters a different phrase for the same ID, the interface will not be able to determine they are equivalent.

5. Selecting an Adjective (optional)

A curator can add an adjective to the Mode of Inheritance by choosing from the selection available in the pull-down.

NOTE: Currently, once a Gene:Disease Record has been created, the disease can be altered up until a PMID has been added. However, the gene, mode of inheritance, and adjective cannot be altered after the record has been created. Please be certain you have selected the desired fields correctly from the beginning.

STARTING GENE-DISEASE CURATION

1. Curation Central view

This is the landing page/homepage for each Gene-Disease curation.

a. First line of header shows the Gene Symbol and Disease selected by a curator.

b. Second line of header shows the Mode of Inheritance selected by a curator. If a curator selected an adjective then this will appear in parentheses.

c. Curation Central home – available from all pages.

d. History of the last saved Summary and any Provisional Classifications for the Gene-Disease record.

e. View Classification Matrix – available from all pages.

f. Gene symbol and links to HGNC and NCBI Gene.

g. Disease name and links to disease term and OMIM.

h. The name of the curator who first created the Gene-Disease record and the timestamp of when they did so.

i. List of all participants who have made edits to the Gene-Disease record.

j. Curator name and timestamp for the most recent edit to the Gene-Disease record.

2. Adding a PubMed article to the Gene-Disease Record

i. To add a PubMed article to the Gene-Disease record click the “Add New PMID” button .

ii. Enter the PMID into the modal that appears and click the “Retrieve PubMed Article” button.

iii. Based on the PMID entered the authors, title, and citation details will be auto-filled. If these details are correct then a curator can add that PMID to the Gene-Disease Record by clicking the “Add Article” button.

iv. The PMID has now been added to the Curation Central view for that Gene-Disease Record.

a. All articles that have been added to the record can be found in a scrollable panel on the left-hand side, with the first author, title, citation details, and PMID shown for each article. By default a newly added article will be the one selected for curation in the interface, as shown by a blue border. To select an alternative article for curation, a curator simply needs to click on that article in the left-hand panel.

b. The central panel shows more details about the article selected by a curator, including all authors, the title, a link to PubMed, and the full abstract.

c. An evidence curation palette on the right-hand side provides now provides access to curation resources for adding Genetic and Experimental Evidence found in the selected article.

d. Further articles can be added to the Gene-Disease Record by clicking the “Add New PMID” button.

3. Starting Evidence Collection

The gene curation palette on the right-hand side is the starting point for adding evidence for a selected article. To begin curation a curator clicks the ‘+’ sign next to specific type of evidence they wish to curate.

ADDING GENETIC EVIDENCE

1. Curate Group Information

The top of the landing page to Curate Group Information shows the authors, title, and citation details for the selected PubMed article in a yellow box below the header. A curator is required to enter a label for the Group, if possible using a label described in the paper.

The rest of the Curate Group Information page is split into relevant sections based on the type of evidence:

i. Group – Common Disease(s) & Phenotype(s)

A curator is required to enter at least one of the following to describe disease(s)/phenotype(s) common to the group:

a) MonDO ID (or free text)

b) HPO ID(s)

c) Phenotype free text

ii. Group – Demographics

Enter information about the demographics of the group.

iii. Group – Information

Enter information about the individuals in the group. A curator is required to enter the total number of individuals in the group.

iv. Group – Methods

Enter information about the methods used to obtain genetic data for the Group.

v. Group – Additional Information

Enter any additional information about the Group.

vi. Cancel/Save buttons

  • Clicking the “Cancel” button, found at the bottom of the Curate Group Information page, will return a curator to the Record Curation page without saving any entered data.

  • Clicking the “Save” button, found at the bottom of the Curate Group Information page, is the only way to save all the Group data added by a curator. Navigating away from this page without saving will result in the loss of any entered data.

  • After clicking the “Save” button if any of the required fields (described above) are not filled in, then a red text warning will appear next to the buttons.

  • Additionally, a red text warning will appear next to the required fields that need to be curated before the page can be saved.

2. Curate Family Information

If the Family to be entered is part of a Group already curated in this Gene-Disease Record then it can be added when prompted after saving a Group by selecting ‘Yes’ from the pull-down, and then ‘Add New Family for this Group’:

It can also be added directly from that Group in the curation palette on the Record page.

To add a new Family that is not associated with a Group, click the Family ‘+’ in the curation palette.

The top of the landing page to Curate Family Information shows the authors, title, and citation details for the selected PubMed article in a yellow box below the header. A curator is required to enter a label for the Family, if possible using a label described in the paper.

The rest of 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:

i. Family – Disease(s) & Phenotype(s)

ii. Family – Demographics

iii. Family – Methods

iv. Family – Segregation. This section is split into two separate sections for adding information on tested individuals and LOD score respectively.

Fields for entering information on Tested Individuals within a Family:

a) For a Dominant and Recessive disease/phenotype a curator is required to enter the total number of AFFECTED individuals in the Family WITH the genotype for that disease/phenotype.

b) For a Recessive disease/phenotype a curator is required to enter the total number of UNAFFECTED individuals in the Family WITHOUT the biallelic genotype for that disease/phenotype.

c) Enter the total number of segregations reported for the Family.

d) If there are any inconsistent segregations amongst the TESTED Individuals then ‘Yes’ should be selected from the pull-down. If not, then select ‘No’.

e) If ‘Yes’ is selected in the prior field then optional free text can be added here to describe the inconsistent segregations.

f) If the Family is consanguineous then ‘Yes’ should be selected from the pull-down. If not, then select ‘No’. If this is unknown then selected ‘Not Specified’.

g) If a pedigree was provided in the publication, then optional free text can be added here to describe the location of the pedigree within the paper.

For entering information on a LOD Score for the Family, there are two separate scenarios based on whether the LOD score was published in the paper or not.

Published LOD Score

If the entered published LOD score should be included in the final aggregate calculation then ‘Yes’ must be selected from the pull-down. If the entered published LOD score should NOT be included in the final aggregate calculation then ‘NO’ should be selected from the pull-down.

A box is provided to add free text to ‘Explain reasoning’ behind this decision. A further free text box allows ‘Additional Segregation Information’ to be entered.

Estimated LOD Score

If there is no Published LOD Score then Select ‘No’ from the pull-down. If the required Tested Individual fields (above) have been entered then the Estimated LOD score will be calculated automatically within the interface.

If the estimated LOD score should be included in the final aggregate calculation then ‘Yes’ must be selected from the pull-down.

If the estimated LOD score should NOT be included in the final aggregate calculation then ‘NO’ should be selected from the pull-down.

A box is provided to add free text to ‘Explain reasoning’ behind this decision. A further free text box allows ‘Additional Segregation Information’ to be entered.

v. Family – Variant(s) Segregating with Proband

To score the proband for a Family then, in addition to the LOD score for the segregation, an Individual proband will need to be created including adding their associated variant(s).

a. A curator is required to enter a label for the Proband, if possible using a label described in the paper. A real name should not be entered.

b. The disease ID(s) for the disease(s) associated with the Family automatically shown.

c. Enter the disease ID(s) for the disease(s) associated with the Individual.

d. Click this button to automatically copy the disease ID(s) for the disease(s) associated with the Family to the field above for the Individual.

e. Check this box if the Individual is homozygous.

f. Check this box if the Individual is hemizygous.

g. Click this button to add the first variant associated with the Individual via a ClinVar ID.

h. Click this button to add the first variant associated with the Individual via a ClinGen Allele Registry CA ID.

i. Click this button to add a second variant (where appropriate) associated with the Individual via a ClinVar ID.

j. Click this button to add a second variant (where appropriate) associated with the Individual via a ClinGen Allele Registry CA ID.

Adding Variants

When adding a Variant associated with an Individual via the ‘Add ClinVar ID’ or ‘Add CA ID’ buttons, a pop-up window will appear. Enter the ClinVar ID or CA ID into the window and click the ‘Retrieve from ClinVar’ or ‘Retrieve from ClinGen Allele Registry’ button respectively.

Check the evidence retrieved for either the ClinVar ID or CA ID you have entered and once you are convinced the ID you have entered represents the correct variant, Select ‘Save’ to add that variant to the Individual.

The variants added via the ClinVar and/or CA IDs can now be seen associated with the Proband:

a. ClinVar Variation ID with linkout to ClinVar.

b. ClinVar Preferred Title for the variant.

c. Link within the Interface to ‘Curate Variant Information’ so that curator can enter the gene impact for that variant. (Please note: this feature was removed, but will be added back shortly.)

NOTE: A variant’s gene impact should be specified in order to score the Proband.

d. Link within the Interfaces to the ‘Evidence View’ in the Variant Curation Interface so that curator can view all known evidence (both programmatic and manually entered from papers) for that variant.

e. Clear the selected variant.

f. ClinGen Allele Registry ID with linkout to the ClinGen Allele Registry.

g. HGVS Title for the current genome build. Shown only of for novel variant that cannot be found in ClinVar and don't have an unambiguous canonical transcript that can be used.

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

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

Once variants have been saved to a Gene Record they will appear in the Gene Record page under the header in a Gene-Disease Records Variants section. There is an individual blue box for each variant containing the name for each variant. Each box is a link to a page for curating the variant’s gene impact.

vi. Family – Cancel/Save buttons

  • Clicking the “Cancel” button, found at the bottom of the Curate Family Information page, will return a curator to the Record Curation page without saving any entered data.

  • Clicking the “Save” button, found at the bottom of the Curate Family Information page, is the only way to save all the Family data added by a curator. Navigating away from this page without saving will result in the loss of any entered data.

  • After clicking the “Save” button if any of the required fields (described above) are not filled in, then a red text warning will appear next to the buttons.

  • A red text warning will appear next to the missing required field.

3. Curate Individual Information

A Proband Individual can be associated with a Family during the Curate Family Information process (as shown above). Upon saving the Family you can:

a. Score and/or Add information about the Proband entered with the Family (‘Scoring Probands’ discussed later)

b. Add a non-proband Individual to this Family.

c. Return to Record Curation page.

Information about Individuals can also be entered at any time from the Curation palette on the Record Curation page:

a. If the Individual to be entered is part of a Group already curated in this Gene-Disease Record then it can be added from this link within that Group.

b. If the Individual to be entered is part of a Family already curated in this Gene-Disease Record then it can be added from this link within that Family.

c. To add a new Individual that is not associated with an exiting Group or Family, click the Individual ‘+’ in the curation palette.

d. To Edit the Information already added for an existing Individual.

The top of the landing page to Curate Individual Information shows the authors, title, and citation details for the selected PubMed article in a yellow box below the header.

a. A curator is required to enter a label for the Individual, if possible using a label described in the paper. If Editing a pre-existing Individual then this Label will already be filled in but can be changed here.

b. A curator must then select ‘Yes’ if the Individual is a proband and ‘No’ if the Individual is a non-proband.

c. Selecting ‘Yes’ will make the disease field a required field.

The Curate Individual Information page is split into relevant sections based on the type of evidence:

i. Individual – Disease & Phenotype(s)

ii. Individual – Demographics

Enter information about the demographics of the group. The ‘Sex’ of an Individual is a required field; extensive options are via a pull-down.

iii. Individual – Methods

iv. Individual – Associated Variant(s)

See the section ‘Adding Variants’ above, which describes how to add Variants using either a ClinVar Variation ID(s) and/or ClinGen Allele Registry CA ID(s).

v. Individual – Additional Information

vi. Individual – Score Proband

Scoring Probands

In order to score a proband, a curator must:

a. Associate the proband with at least one variant in the ‘Individual – Associated Variant(s)’ section above.

b. Specify the gene impact for each variant associate with the proband. To do so, the curator should click on the ‘Curate variant’s gene impact’ link under the variant.

c. After following the link, a curator is required to select the gene impact for the variant from the pull-down. [Please note: this feature was removed, but will be added back shortly]

d. Each variant that has had its gene impact assessed is marked with a white box next to its variant name in the Gene-Disease Records Variants section of the Record Curation page.

e. Upon saving the gene impact for all the variants associated with a proband, you can return to the Edit Individual Information page and will now be able to Score the proband via a pull-down selection (Score, Review or Contradicts).

f. The case type must then be confirmed from the pull-down. Note: The default score and range of choice if choosing a different score will change depending on this case type choice.

g. If a curator chooses a different score from the default score then they are required to explain their reasoning in the box provided.

4. Curate Case Control Information

To add Case Control data to a record click on the ‘+’ in the curation palette on the Record Curation page.

The top of the landing page to Curate Group Information shows the authors, title, and citation details for the selected PubMed article in a yellow box below the header. A curator is required to enter a label for the Case-Control, the Case Cohort and the Control Cohort.

Upon saving the gene impact for all the variants associated with a proband, you can return to the Edit Individual Information page and will now be able to Score the proband via a pull

i. Case Cohort – Disease(s) and Phenotype(s)

A curator is required to enter at least one of the following to describe disease(s)/phenotype(s) common to the Case Cohort:

a) MonDO ID(s)

b) HPO ID(s)

c) Phenotype free text

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

ii. Case Cohort/ Control Cohort – Demographics

iii. Case Cohort/ Control Cohort – Methods

iv. Case Cohort/ Control Cohort – Power

v. Case Cohort/ Control Cohort – Additional Information

For instance:

Then the Case Control Evaluation section is for evaluating the evidence on the Case Control group as a whole.

vi. Case Control Evaluation – Statistics

vii. Case Control Evaluation – Bias Category

viii. Case Control Evaluation – Comments

ix. Case Control – Score

Scoring Case Control

In order to score Case Control, a curator must select a Score from the pull-down and the click Save.

ADDING EXPERIMENTAL EVIDENCE

1. Curate Experimental Information

To add Experimental data to a record click on the ‘+’ in the curation palette on the Record Curation page.

A curator is first required to select the Experiment Type from a pull-down:

There are six different curation experiences dependent on the Experiment Type selected by the curator.

i. Experimental – Biochemical Function (A) and (B)

The ‘Biochemical Function’ option has two separate options, A and B, provided in a pull-down.

Both have a number of required fields, shown with an asterisk next to the field. One of these required fields is for adding the Gene Ontology (GO) ID that best defines the function of the gene in the Record.

Adding GO IDs

In order to aid the curator in searching for the correct GO ID, there are 3 links provided – one to view existing GO annotations for the gene, one that links to the OLS GO Search, and one that links to Quick GO

a) Only choose either “Molecular Function” or “Biological Process”

b) Only choose manual experimental evidence, e.g. codes IDA, IMP, IGI, IPI and IEP. Other codes may be inferred, e.g. IEA which is ‘Inferred by electronic annotation’

c) As you go down a GO tree the terms become more specific, only go down the tree as far as you feel secure in your decision.

d) If you are not sure which specific GO term to add then go back up the tree until you find a general term that fits your knowledge.

Scoring Experimental Evidence

Experimental data can be scored via a pull-down selection (Score, Review or Contradicts) in Experimental Data Score sections found at the foot of every Curate Experimental Data Information page.

The default score and range of choice if choosing a different score will change depending on the experimental data type.

If a curator chooses a different score from the default score then they are required to explain their reasoning in the box provided.

ii. Experimental – Protein Interactions

Has a number of required fields, shown with an asterisk next to the field.

iii. Experimental – Expression (A and B)

The ‘Expression’ option has two separate options, A and B, provided in a pull-down.

Both have a number of required fields, shown with an asterisk next to the field. One of these required fields is for adding an anatomical structure Ontology (UBERON) ID that best defines the organ or tissue relevant to the gene expression evidence. A link out to UBERON has been provided to aid in searching for the correct ID.

iv. Experimental – Functional Alteration

Has a number of required fields, shown with an asterisk next to the field.

Includes section for adding variant(s) associated with this data type. Simply click on “Add variant associated with Experimental data’. A pop-up window will appear whereby variants can be added via either a ClinVar VariationID or a ClinGen Allele Registry CA ID.

Variants can then be added via either a ClinVar Variation ID or a ClinGen Allele Registry CA ID.

v. Experimental – Model Systems

Has a number of required fields, shown with an asterisk next to the field.

Including selecting whether it is a non-human model organism or cell culture model, and the associated ‘Description of gene alteration’.

If ‘Cell culture model’ is selected then cell culture model type/line becomes a required field. This field can accept either an Experimental Factor Ontology (EFO) ID or a Cell Ontology (CL) ID. Links out to EFO and CL ontologies within the ontology lookup service (OLS) have been provided to aid in searching for the correct ID.

Also includes section for adding variant(s) associated with this data type.

vi. Experimental – Rescue

Has a number of required fields, shown with an asterisk next to the field. For instance:

Includes section for adding variant(s) associated with this data type.

THE CLASSIFICATION MATRIX

1. Viewing the Classification Matrix

To view the Classification Matrix click on the ‘View Classification Matrix’ button found in the left upper header on each page. This will generate the Matrix for the current saved evidence and scores:

The top of the resulting page contains the Classification Matrix

  1. Automated upper Calculated Classification Matrix (Note: this matrix represents the saved evidence and scores at the time you clicked the “View Classification Matrix button)

2. Classification Matrix Features

For each specific evidence type there are the following columns rows (see graphic on next page to see where each item, below, is found in the matrix):

a. Evidence Type – brief description of types of evidence scored upon.

b. Count - total number of pieces of evidence scored for the Evidence Type listed

c. Total Points – the total number of points for all the pieces of evidence scored for that Evidence Type; if the maximum points allowed is reached, the number of points displayed will be the maximum value

d. Points Counted – the total of all the scores added together for each section; if the maximum points allowed is reached, the number of points displayed will be the maximum value (for each specific type of evidence there is a maximum number of points allowable, see the SOP for allowed max scores).

Each specific evidence type is shown in rows (see graphic on next page to see where each item, below, is found in the matrix):

e. Variant/proband scores, if curating an autosomal dominant disease or an X-linked disorder

f. Variant/proband scores, if curating an autosomal recessive disease.

g. Case level segregation scores

h. Case Control scores

i. Genetic Evidence Total. The total number of allowable points for genetic evidence. Calculated by adding the ‘Points Counted’ for each of the genetic evidence types NOTE: Maximum points allowed for this field is 12

j. Experimental (functional) scores

  • Biochemical Functions
  • Protein Interactions
  • Expression

k. Experimental (functional alteration) scores

  • Patient cells
  • Non-patient cells

l. Experimental (model) scores

a. Non-human model organism

b. Cell culture model

m. Experimental (rescue) scores

  • Rescue in human

  • Rescue in non-human model organism

  • Rescue in cell culture model

  • Rescue in patient cells

n. Experimental Evidence Total. The total number of allowable points for experimental evidence. Calculated by adding the ‘Points Counted’ for each of the experimental evidence types

o. Total Points. The sum of the Genetic Evidence Total and Experimental Evidence Total.

For Segregation Evidence, the Total Points field additionally contains the LOD score in parentheses. If the LOD score has been generated by summing multiple LOD scores then it will have an asterisk.

SAVING & MODIFYING A SUMMARY CLASSIFICATION

NOTE: Modifying and then saving a Classification in the panel just below the Classification Matrix will NOT mark it as Provisional or Approved, but will bring up the option to save it as Provisional_.

1. Modifying a Classification

(see graphic below to visualize where each item listed below is found on the Save Classification panel)

a. Genetic Evidence Total assigned points.

b. Experimental Evidence Total assigned points

c. Total Points

d. Replication Over Time. Tickbox to identify whether the evidence has been replicated over time. Tick for ‘Yes’, leave blank for ‘No’. (Note: this can change the Calculated Classification; to upgrade a 12-18 Total Points from a Strong to Definitive classification then ‘Yes’ must have been selected for Replication Over Time.

e. Calculated Classification is automatically filled in based on the Total Points, including your answer to “Replication Over Time?” The calculated classification is highlighted in blue.

f. Contradictory Evidence. If a Proband or Experimental evidence has been scored as Contradictory by the curator then it will have a red ‘Yes’, if not it will have a black ‘No’.

g. Curators can modify the Calculated Clinical Validity Classification by selecting an alternative Classification from the pull-down options.

h. If the curator has modified the Classification then they are required to explain their reasoning here.

i. Evidence Summary – this free text box allows curators to summarize their evidence and provide a rationale for the clinical validity.

j. Last Saved Summary Classification (i.e. Classification value saved previously, before clicking “Save”)

k. Timestamp when current Last Saved Summary Classification was saved, if previously saved

2. Saving a Summary Classification

Clicking the “Save” button at the bottom of the Save Classification table will save the Classification (see above figure). The Calculated Classification will be saved by default as the Classification, unless a modification has been selected. NOTE: Saving a Classification at this step is NOT marking it as Provisional or Approved, but will bring up the option to save it as Provisional (see section below on saving as Provisional and Approved).

Upon saving the bottom of the page will be updated to a View only option to reflect the saved options. Check that everything looks correct

a. Classification value just saved (when “Save” was clicked).

b. Timestamp for the Classification value (a).

c. Link back to the Record Curation page.

d. Option to unlock the Save Classification section for re-editing (i.e. to change the modification, update the reason(s) for change text, mark as provisional, and/or update the evidence summary text).

e. View the Evidence Summary for this saved Classification for the Gene:Disease record.

Once you have saved a Summary Classification, you will see it highlighted in the header; the Classification becomes "In Progress" and a "New Saved Summary" tag appears:

With every visit to the "View Classification Matrix" page, the three editable fields in the Modify/Save Classification table are available to be edited 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). Note: The Save button must be clicked to save any edits to the current Summary Classification value.

If the new calculated Total Points now suggests a calculated Classification that is the same as a Modification saved on the last visit, then that Modification will be reset to “No Modification” and there will be a red warning message to explain this.

After saving a Classification, the option to Save it as a Provisional will appear:

Note: Please see "Saving as Provisional and Approved" Section below for information on moving a Classification to Provisional or Approved status.

3. Revisiting the Classification Matrix

Every time a curator visits the Classification Matrix (regardless as to whether a Classification has previously been saved, or saved as Provisional or Approved), all the scores in the upper Calculated Classification table are recalculated based on the current set of saved evidence and associated saved scores. You will see a yellow box below that table that explains this.

Note: Please see "Saving as Provisional and Approved" Section below for information on moving a Classification to Provisional or Approved status.

EVIDENCE SUMMARY

1. Evidence Summary Header:

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.

The Evidence Summary will pop up as a new tab or window. Be sure to close it when you are finished. There is a close button at the top of the page as well as the bottom, just so you do not get confused the next time you generate an Evidence Summary:

The Evidence Summary table header contains a summary of information about the saved Classification:

2. Evidence Summary tables

The Evidence Summary summarizes and sorts all the evidence for the saved Classification into tables according the evidence types (Case Level, Case Level for segregation evidence when there is no associated proband, Case-Control, and Experimental). Note that evidence that is has a score status of “Score,” “Review,” or “Contradicts” is shown. For the total points shown at the bottom of each evidence table, only those rows of evidence where the score status was set as “Score” are included in the calculation.

See next page for the various tables of evidence in the Evidence Summary

  Case Level Data:

Case Control Data:

Experimental Data:

3. Printing Evidence Summary & Saving as PDF.

When printing this view, we recommend the following print settings:

• "Landscape" for layout

• 50% for Scale

• "Minimum" for Margins

• Select "Background graphics"

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

SAVING AS PROVISIONAL AND APPROVED

1. What do Provisional and Approved Mean?

The option to save as Provisional appears after saving a Summary Classification. The option to save as Approved appears after saving a Classification as Provisional.

  • Provisional: Curator has marked the Classification as complete and ready for review
  • Approved: Provisional Classification has been reviewed and approved by a previously designated Approver

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

2. Saving as Provisional

After saving a Classification, the option to Save it as a Provisional will appear (see bottom panel of figure below):

If the curator is curating as part of an Affiliation, this will be printed out "automatically." The curator who is saving the Classification as Provisional will be printed out upon submitting the form. The curator can add the date reviewed for Provisional Classification as well as additional comments pertaining to this review process. The timestamp of the submission will be saved and equivalent to the time at which the Provisional Classification is saved (Note: this could be different from the Date of Review).

Upon clicking "Preview Provisional" (a Preview step is required as Provisional Classifications cannot be edited -- new Provisional Classifications can be made), 3 options will appear:

  1. Cancel Provisional: resets all Provisional fields

  2. Edit Provisional: allows you to edit the information entered (date, additional comments)

  3. Submit Provisional: saves Provisional Classification -- once saved, no edits can be made, but the Evidence Summary for the Provisional Classification can always be viewed. If a second Provisional Classification is made, the first one will be archived, and its Evidence Summary will remain viewable (see below)

When a curator saves a new Provisional Classification, they will see an entry for it, with the ability to "View Provisional Summary" as well as an Approval box appear above. Clicking on the "View Provisional Summary" button will show you the Evidence Summary for your saved Provisional Classification. Note: This Provisional Classification cannot be edited, but it can always be viewed, even if a new Provisional Classification is saved.

On the banner underneath the header of each page in the GCI, you will also see the Provisional tag appear; if you are on the Record Curation Central page, you will also see "[View/Approve Current Provisional]" -- you can click on this to get back to the Approval form shown above.

NOTE: If changes are required following review of a Provisional Classification prior to approval, please follow the following steps:

  1. Add evidence
  2. View Classification Matrix
  3. Save new Summary Classification
  4. Create new Provisional -- this new one will become the current Provisional and the previous Provisional will become archived

3. Saving as Approved

When your Saved Provisional is ready to be Approved, you can Approve the Current Saved Provisional by clicking on the "[View/Approve Current Provisional]" link from the Record Curation Central page (or Approve it directly after saving the Provisional. Fill in the forms, much as was done when saving the Provisional:

Note that, if certain people have been designated to be an "Approver," their names will appear in the pull-down and this will be a required field.

Once you select "Preview Approval," you will be able to see the information (date, approver, additional comments) for the Approval and then, as for saving a Provisional, pick one of the 3 options:

  1. Cancel Approval: resets all Approval fields

  2. Edit Approval: allows you to edit the information entered (date, approver, additional comments)

  3. Submit Approval: saves Approved Classification -- once saved, no edits can be made, but the Evidence Summary for the Approved Classification can always be viewed. If a second Approved Classification is made, the first one will be archived, and its Evidence Summary will remain viewable (see below)

Once an Approved Classification is submitted, it will appear directly above the current saved Provisional (both will be marked with green flags). You will be able to see the Approved Classification at any time by clicking on the "View Approved Summary" button. Note: This Approved Classification cannot be edited, but it can always be viewed, even if a new Approved Classification is saved and it becomes archived.

Once a Classification has been Approved, this tag will appear in the header

4. Creating New Provisional and Approved Classifications

Once either a Provisional or Approved Classification has been saved, a curator can still adjust evaluations or add new evidence and evaluate that evidence to create a New Saved Summary and then a new Provisional and Approved, if desired.

While new saved Summary Classifications will replace previous Summary Classifications, new Provisional and Approved Classifications will NOT replace/override their previous Provisional or Approved Classifications -- all previous Provisional and Approved Classifications will be archived, and their summaries viewable at any time via the "View Provisional Summary" and "View Approved Summary" buttons.

If new evaluations are made following Approval and a new Summary Classification is saved, the "New Saved Summary" button will also appear in the header

If this new saved Summary Classification (with or without modification) is saved as Provisional and an Approved Classification already exists, the new Provisional Classification will appear at the top with a green flag to mark it as the current Provisional Classification:

The New provisional button will appear in the header alongside the Approved button to indicate a new Provisional Classification has been made since the Approved one:

If on the Record Curation Central page, you will also see the ability to view the Evidence Summary for your current Approved Classification or to View or Approve the Current Provisional (New Provisional).

PUBLISHING APPROVED CLASSIFICATIONS TO THE CLINGEN WEBSITE

1. Before Publishing

  1. Gene Curation Express, which was previously used by ClinGen curators to enter Classifications from spreadsheets onto the ClinGen website, was disabled when the "Publish" feature went live as part of release 20 (R20) of the GCI/VCI. From this point on all submissions of Approved Classifications to the ClinGen website need to be done only via the "Publish" feature in the GCI. If you wish to amend any of the Classifications that were added to the ClinGen website via Gene Curation Express, this will need to be requested via the ClinGen website help desk (clingen@clinicalgenome.org).

  2. Only Classifications with an 'Autosomal Dominant', 'Autosomal Recessive', or 'X-linked' mode of inheritance (i.e. those supported by the Clinical Validity Classification framework) should be published to the ClinGen website. Classifications with an "Unknown" or "Other" mode of inheritance will encounter an error. Additionally, as mitochondrial inheritance is not currently supported by the Classification framework, Classifications with mitochondrial inheritance should not be published to the website. The Gene Curation WG will work with the mitochondrial gene curation group to provide the ability to support this in the future.

  3. Currently, the disease for a Gene:Disease Classification must be annotated using a MONDO ID for that Classification to be successfully published to the website. Right now, Classifications with a free text term will encounter an error when one tries to publish them to the website. We are working to support the publication of free text disease terms on the website in the near future; however, MONDO IDs are still strongly encouraged whenever possible. If you are having trouble finding a MONDO term for your disease, please reach out to clingen-helpdesk@lists.stanford.edu and we will direct you appropriately.

2. Who Can Publish?

Any user curating as part of a ClinGen Affiliation can publish to the ClinGen website (clinicalgenome.org). Publishing is currently restricted to ClinGen Affiliations only.

3. How to Publish

If you have migrated away from the Classification section then when you return you can open the "Publication Classification" panel by clicking the "Publish Summary" button associated with the current Approved Classification.

Alternatively, upon saving an Approved Classification a "Publish Classification" panel automatically opens up above the "Saved Approved and Provisional Classification(s)" table.

Most fields will be auto-filled but you do have the option of adding in any comments about the publishing process in the "Additional comments" box. To proceed with publishing click the "Preview Publish" button.

Once you select "Preview Publish," you will be able to see the information (affiliation, date published, publisher, additional comments) for the publication and then, as for saving a Provisional or Approved Classification, you can pick one of 3 options:

  1. Cancel Publish: resets all Publish fields
  2. Edit: allows you to edit the information entered (additional comments)
  3. Publish: publishes the Approved Classification to the ClinGen website -- once saved, no edits can be made.

Upon publishing, you will now see information about the Publish process in a panel under the Approved Classification to which it pertains. This panel contains information on who the Approved Classification was "Published by", its "Date published", any "Additional comments" that were saved, and a "Link" that is a direct linkout to the Approved Classification on the ClinGen website.

NOTE: although the newly published Approved Classification will appear almost immediately on the ClinGen website, it may take several minutes before it will appear in searches and/or lists.

The purple "PUBLISHED" icon is used to indicate that an Approved Classification has been published, it can be seen in the headers and on the dashboard.

If the Published Approved Classification is not the most recent Approved Classification, i.e. since it was published a new Classification has been Approved but not yet Published, then a purple warning triangle will be shown next to the purple "PUBLISHED" icon.

4. How to Unpublish

There are two ways to Unpublish an Approved Classification:

  1. If a second Approved Classification is published, the first one will be automatically unpublished. Details of the Unpublishing are shown below the now archived (previously Approved) Classification, such as who it was "Unpublished by", its "Date unpublished", and any "Additional comments" that were saved. It's unpublished status is also indicated by the "UNPUBLISHED" icon.

  2. A current Published Approved Classification can be Unpublished at any time simply by clicking on the "Unpublish Summary" button found under that Classification.

Upon clicking the "Unpublish Summary" button an "Unpublish Classification" panel opens up above the "Saved Approved and Provisional Classification(s)" table.

Most fields will be auto-filled but you do have the option of adding in any comments about the unpublishing process in the "Additional comments" box. To proceed with unpublishing click the "Preview Unpublish" button.

Once you select "Preview Unpublish," you will be able to see the information (affiliation, date unpublished, unpublished by, additional comments) for the unpublication and then, as for publishing an Approved Classification, you can pick one of 3 options:

  1. Cancel Unpublish: resets all Unpublish fields

  2. Edit: allows you to edit the information entered (additional comments)

  3. Unpublish: unpublishes the Approved Classification from the ClinGen website -- once saved, no edits can be made.

Details of the Unpublishing are shown below the now archived (previously Approved) Classification, such as who it was "Unpublished by", its "Date unpublished", and any "Additional comments" that were saved. Its unpublished status is also indicated by the "UNPUBLISHED" icon.

NOTE: it may take several minutes before the Classification disappears from all locations on the ClinGen website, so please allow up to 15 minutes before confirming that it has been unpublished.

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