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).
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.
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.
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.
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.
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.
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: