Hello, everybody. This is Peter Cooper, from the NCBI service desk and welcome to another
NCBI webinar. One of the shorter ones, the one that we call the NCBI minute so we will
talk about 10 minutes here. Some reminders, and that is what this slide is for. Recording
of this webinar will be available on the YouTube channel and it will take us about 10 days
to get that up there. The materials, which basically our backup slides, kind of screenshots
that we will show you, are available on the FTP site and that compressed URL will take
you to those materials. Today Melissa Landrum, who is the lead developer for the ClinVar
resource is going to be talking about the new ClinVar submission wizard and I am going
to turn it over to Melissa right now.
Thank you, Peter, and hello everyone, thank you for joining us today. ClinVar is the NCBI
database for archiving interpretations of variants relative to diseases and other phenotypes.
All interpretations in ClinVar are provided by our submitters, including clinical testing
labs, research labs, resources like OMIM, GeneReviews and locus specific databases as
well as expert panels and practice guidelines.
A link to information on how to submit to ClinVar is available from the ClinVar homepage.
Submitters who have several interpretations to submit or submitters that submit repeatedly
like clinical testing labs use our submissions spreadsheet templates and there is a section
on this page with information about those templates. For researchers and other submitters
who submit a single variant at a time, it may be easier to use the ClinVar submission
wizard to guide you through the submission process. For example, a genetic counselor
may review a variant in a lab report and want to submit her own interpretation to ClinVar
or a research lab might be publishing a paper on a new causative variant for a disease.
To get to the wizard from this page, you can click on how to submit, and you will see a
link here to NCBI's Variation Submission Portal. We will click on that. Also note that you
can get to the submission portal from the NCBI homepage.
For this demonstration today, I will switch to an internal site, but note that when you
use the submission portal, you will not need to make any changes to the URL. When you first
log into the Variation Submission Portal, you will need to register your organization.
You can use this help link at the top of the page if you need more information to do that.
Once your organization is registered and approved, on this page, you will see the name of your
organization, so -- this is the demo -- by organization name is ClinVar submission test
lab. That will be followed by two buttons, one for the ClinVar a single submission wizard,
and the second is to upload a new file submission like a spreadsheet.
So today, we are going to click on the button for the submission wizard. The wizard walks
you through a series of tabs for different kinds of information. The first tab is for
general information about your submission. Here you will provide a name for the submission,
which is just for your own use in submission portal. You can use the name that is provided
or you can give your own name, so today, I'm going to submit a variant that causes CFC
syndrome so I am going to name the syndrome CFC 1 variant 1. If your submission is part
of a named to study like the seizure project or that Framingham study, you can provide
the name and a description of the study in these boxes.
If your submission is from a standalone research project, you can leave these boxes blank.
You can let us know if you need your submission held until the corresponding paper is published
by selecting hold until published here. For this example, I'm going to select public so
that my submission is not held. If the citation is already available, you can provide that
information in this section. So today, for my demonstration, I am going to provide a
publication using a pub med ID. Note that on each tab, your work is not saved until
you click the save and continue button, but that means that you can start a submission,
save your work for one or more tabs and come back to the form later to complete the process
so I will click save and continue. That takes us into the next tab, where you can indicate
which organization should get attribution for this submission. If your submission is
from a single organization, like a single research lab, you can select single organization
here and save immediately the organization for which you have logged on will be used
automatically. If your submission is for multiple groups, each of those groups needs to be registered
and approved in the submission portal first and you will need to have been defined as
a submitter for each organization. Then, when you select multiple organizations, all of
those groups are available in this table. One should be specified as the primary organization
for the ClinVar submission and any number of others can be specified as additional organizations.
For today's example I am going to submit from a single organization. Use the next tab to
define the variant that you have interpreted. The interpreted variant may be a single variant,
like a single nucleotide substitution, two single variant as a compound heterozygote,
or multiple variants in cis as a haplotype.
To describe the location of the variant and the change that you observed, you can use
either HGVS nomenclature or chromosome coordinates here called sequence location. When you select
the types of variant and method of description, the page updates to provide the appropriate
field for you to fill in. For this example, I am submitting a single variant in the b-raf
gene so I'm going to describe with an HGVS expression so I will fill in the reference
sequence with accession and version. A description of the sequence change, so that would be the
c. or g. of an HGVS expression. I am going to fill in the gene. Note that you can start
typing the gene symbol and you will get a list from which to choose. I'm going to provide
an alternate designation. Here, this is the protein name, but this could be any other
name by which that variant is known including other nucleotide descriptions with legacy
numbering systems. There are other optional fields to fill in. You can provide a variation
identifier like a dbSNP or rs number or the location of the variant so the intron or exon
that it is in, your local identifier for the variant if you have a database, or the functional
consequence. Note that most of these fields on this tab are optional so you can just fill
in the information that you have.
Variants in ClinVar are generally interpreted with respect to a disease or condition so
this condition is indicated on the conditions tab. If you have information to submit on
observed phenotypes or clinical features, please wait to submit them on the observations
tab. The condition for which you are interpreting of the variant can be described with a database
identifier like a OMIM number. Or you can provide the name of the disease in this box.
In some cases, a variant is submitted to describe its effect on a person's response to a drug,
so for these cases, you can select drug response here, and the page updates to let you enter
the drug name, and optionally, the condition for which that drug is used. For this example,
I'm going to submit on the disease, CFC 1 syndrome and I'm going to do so with an OMIM
number.
Use this tab to describe your interpretation of the clinical significance of the variant.
You must provide a value for the clinical significance of the options for that are available
in this pulldown menu. I am going to submit that this variant is likely pathogenic. And
then, optionally, you can also provide other information, such as the mode of inheritance
for that variant, again options are provided in the menu. You can provide the date that
the clinical significance of that variant was last evaluated. And you can also provide
a comment that describes why you classified the variant as you did. This tab also led
to provide information about the method that you used to classify variants which in ClinVar
we call your assertion criteria. More information about this is available on the ClinVar website
using this link. But in short, this is a document that describes the categories that you use
to classify variants such as benign, uncertain and pathogenic and the criteria that you required
to assign a variant to each category. If this information is in your publication describing
the variant, the pub med ID can be provided as the assertion criteria here. We do encourage
submission of assertion criteria if it is available because it affects the review status
or number of stars on the resulting ClinVar record. But it is not required so you can
certainly submit your data to ClinVar without assertion criteria, leaving this section blank.
ClinVar submissions also include the evidence that supports the interpretation in the form
of observations of the variant. Those observations it may be described as aggregates, individuals,
or experimental results. At least one observation is required per submission. If you want to
submit data for many individuals as a group, you can use the aggregate section. You can
submit information about more than one group as distinct aggregates. For example if you
had information from a case-control study, you can complete a section for the cases and
another for the controls. In other words, all of the information in this observation
applies to everyone in this group. If you prefer, you can provide information about
each individual with the variant. So in this case, all of the information is specific to
that person, such as that person's age, their ethnicity, or the phenotypes that were observed
in that individual. For research groups, who have performed functional assays to evaluate
a variant, that experimental evidence can also be described. That information might
include the cell line used in the experiment or the tissue type that was analyzed, and
you can also provide a comment that also describes your experiment. More structured details about
the experimental methods can also be provided. For this example, I am going to submit one
aggregate observation. So this is information about a group of affected individuals for
this disease. I am going to name my observation. I'm going to indicate, yes, that they were
affected with the disease. I am going to indicate that the allele origin was germline, this
variant was detected as a germ line variant, and indicate that the data was collected with
clinical testing. I am also going to indicate that this was seen in a mixed group of males
and females, and the age range for these individuals is from 1 to 20 years. I am going to indicate
that I saw this variant in six families and a total of six single heterozygotes.
When you have entered in your information, make sure to click save and continue and when
you have entered all of your observations, click save and continue. Which takes you to
the final tab. This is an overview of the information that you have provided. You can
take this opportunity to review the data and go back and correct anything if necessary.
Once you are finished, click the submit button at the bottom of the page. This is a critical
step. It sends your data to ClinVar and sends you an email confirming that you have submitted
your data. When we receive the submission, one of the ClinVar curators will check it
and contact you with any questions about the data. Otherwise, your data will be promptly
processed and made available on the ClinVar website. We encourage you to try the ClinVar
Submission Wizard and we welcome your feedback. You can use the contact link at the top of
this page to send us any questions or suggestions about the wizard.
We have time for a few questions. If anyone wants to send those in, we would be happy
to answer them.
The first question that we have is, how do I know if I should use the wizard or use a
spreadsheet to submit to ClinVar?
Our recommendation is that if you are submitting a very small number of variants at a time,
let's say less than 5, it will probably be useful to use the wizard. If you are submitting
more variants, let's say more than 5 or 10 variants, you will get faster processing of
your submission if you use the spreadsheet because that makes it more efficient for the
curator to review many variants at a time and get back to you with any issues so that
it can be processed more quickly.
The second question we have here is, if I find that I have made a mistake in my submission,
can I get in and edit it?
If you have already sent your submission to ClinVar, so here in the table, you can track
the progress of your submission, so this is the one that I just entered and you can see
that the status is submitted. It does not have an edit button here so once you have
already sent it to ClinVar, it is not available to edit. If one of our curators finds something
that needs to be fixed, we will change the status so that there is an edit button here
for you to fix your data. If you have not yet submitted your wizard submission, you
will see an edit button here and you can go in and make any edits until you are ready
to submit.
We have another question. Should people only use the wizard for submissions where they
have made their own assertion on the variant or would clinicians use this to report assertions
directly from lab reports?
You can certainly use it to submit your own assertion of the variant. Whether or not clinicians
can use it to report directly from lab reports. You can certainly, Actually, for that, I would
actually suggest at this point that if you would like to do that, you can use the spreadsheet
and the reason is that the labs themselves may have already submitted that interpretation
to ClinVar and, if you are going to submit somebody elses assertion, we need to know
who the testing laboratory was. So that is a feature that we will add to the wizard in
a future release, but for now, that information can be submitted on the spreadsheet. So if
you would like to submit that kind of information and you need help with the spreadsheet, please
do feel free to contact us.
Okay. This is Peter Cooper. I am back again. Thank you, Melissa. That was great and that
is all we have time for today, so we will have the slides and materials, sort of the
screenshots, available on the webinars and courses page and we will have the recording
up on the YouTube channel probably within 10 days. Thank you, everybody, for coming
and I am going to go ahead and end the webinar.