ClinVar is a freely accessible, public archive of reports of the relationships among human genetic variations and phenotypes, with supporting evidence. Essentially, this means it’s an archive of variants associated with a gene. Variants are submitted typically by major diagnosing laboratories and research centers. Variants are classified as pathogenic (disease causing), benign (not disease causing), and unknown significance (not enough evidence to show the variant is disease causing or not).
How do I see the SYNGAP1 variants in ClinVar?
At the top of the ClinVar home page type “SYNGAP1” into the search:
As of early February 2021, a search for the SYNGAP1 gene in Clinvar yields 533 results.
Does this mean there are a total of 533 officially diagnosed patients with SYNGAP1 Encephalopathy (SYNGAP)?
No. For a number of reasons:
Firstly, the total count includes all variants, including those considered benign, likely benign, or uncertain significance. Individuals with benign variants are not considered to have a disease-causing variant. In other words, a SYNGAP1 variant is not causing their symptoms. All current evidence supports the assertion they do not have SYNGAP. Approximately one third (n=188) of the SYNGAP1 variants listed in ClinVar are considered benign.
Secondly, a decent chunk of listed variants are of uncertain significance (n=147), of which 142 are missense. This means there’s currently not enough evidence to confirm a diagnosis, which complicates the count of identified patients. You can read more about these uncertain variants in our recent blog to see what types of new data will help determine their effect.
Finally we are left with pathogenic and likely pathogenic results which make up around 200 of the variants listed.
Does this mean that there are about 200 people officially diagnosed with SYNGAP?
Again, no. Here’s why:
Each entry in ClinVar is associated with a specific variant and multiple individuals can have the same variant. In the example highlighted, we filter for pathogenic nonsense variants. The first result illustrates there are multiple submitters for that particular variant: Ambry Genetics, Institute of Human Genetics, and Invitae in 2015, 2017 and 2019, respectively. Does that mean there are three people in the world with this variant? Maybe. We can’t be sure because the data are de-identified. It could be the case that the same person was tested at different times through different laboratories.
So can we use ClinVar to approximate the number of officially diagnosed patients?
Not really. ClinVar submissions are entirely voluntary. To list a variant in ClinVar, the laboratory has to go through a submission process, which requires effort. Not every lab or research center has the time, budget, or inclination to submit the variant of every person they test. So all we can say is there are maybe around 200 people whose lab or research center has submitted their test results to Clinvar. But that leaves out a lot of diagnosed patients.
So how do we get a good number of diagnosed patients?
Great question. For many reasons, no SYNGAP patient registry currently contains all the diagnosed patients. Many families do not speak english. Some don’t have a copy of their genetic report. Many simply don’t have the capacity to participate. Does that mean those patients don’t exist? Does it mean they shouldn’t be counted?
The member organizations of the SynGAP Global Network (SRF is the only US member) believe patients should be counted regardless of their access to patient registries. That’s why in 2019 we started the #SyngapCensus. Every quarter we ask each patient organization or local support group: how many? Local organizations know their patient community best. They have FaceBook groups, WhatsApp groups, Weibo pages, vKontact pages, and are often very active! We also become aware of publications that describe diagnosed patients. Our global patient ambassadors perform outreach. They get updates from local neurologists about the number of diagnosed patients in their area and connect with them.
But isn’t this incredibly inaccurate? What’s the point of this count?
We are confident in our collaborative approach and if anything err towards not counting someone if we’re unsure. That being said, the #SyngapCensus was never intended to be a perfect dataset, indeed that’s not its purpose and we make that clear in each update. It’s a best-efforts collaborative estimate.
But it’s very important. Here’s why:
- It helps us reach and support more families. With our support, those families become part of the thriving SGN & SRF community. We advise families how to obtain their genetic report so they can participate in registries and studies. In the US, we rolled out our natural history study with Ciitizen in part to enable our families to have better access and more control over their medical records.
- We get a sense of the rate of diagnosis in different places. For example, more patients in China, India and Turkey have recently started to be diagnosed/come to our attention.
- Professionals have come to rely on rare disease patient organizations to know their community. When we talk about developing a treatment for SYNGAP1 and moving towards clinical trials, one of the most important things is to have an active, engaged and motivated patient community. #SyngapCensus is an indicator of just how well connected we are.