SYNGAP1 Frequent de novo Missense Variant Alert — Study Opportunity for p.Gly344

Mutation: c.1030G>A, p.Gly344Ser

We have identified an apparent hot spot for a de novo missense mutation. We want to share this information with the patient community and researchers to promote and facilitate a heightened focus on this potentially important area, SYNGAP1 missense mutation c.1030G>A, p.Gly344Ser.

The Communication Trail: Connection is everything!

How did we find this group of patients? First, a parent from Portugal reached out to let me know our children had the same missense mutation. When additional missense SYNGAP1 families joined the group, she identified others with the same variant. Shortly thereafter, SRF’s Russian liaison shared the name of another SYNGAP1 patient with the identical variant. Finding and recognizing these “needles in a haystack” emphasizes an SRF saying: Connection is Everything!

‍How is this possible?

How do ten people in the world have the same rare de novo mutation in the same location, and what does that mean for research? Of the first 81 SYNGAP1 mutations in Ciitizen, most have only one example, although there are a few mutations with two to four examples currently identified. Whether you are in the Ciitizen Digital Natural History, or especially if you are not, connecting with SRF to add your variant to our list builds an accurate description of our patient community.

The science of these mutations

p.Gly344 means that a Glycine amino acid is at position 344 in the Syngap protein. Glycine happens to be the smallest amino acid. Its side chain is a single hydrogen atom. The hydrogen in Gly344 is predicted to be used in hydrogen bonding within the protein structure (Figure 2b). Any substitution at p.Gly344 could destabilize the protein since any substitution will be larger than a hydrogen, and would interfere with the modeled hydrogen bond. Does the substitution of Serine (or Valine) destabilize the protein? Is the protein so unstable that the mutant protein is degraded or does it persist in the cell? Is the mutant Serine phosphorylated? A site that can be phosphorylated is a molecular switch, where adding or subtracting a phosphoryl group to the amino acid alters the activity of the protein. (See Wikipedia for more.) Syngap is regulated in this way, and adding another Serine may impact its regulation by phosphorylation. We don’t need guesses, we need real answers.

‍Research. Research. Research.

‍To determine the biological and biochemical consequence of this mutation, research is needed. The ten patient cases with the p.Gly344 missense variant provide a unique opportunity to:

  • Determine whether the mutant protein has a loss or gain of function
  • Determine the expression level of the mutant protein
  • Investigate whether the two alleles can be easily distinguished in patients
  • Potentially identify genetic modifiers that intensify or alleviate the disorder
  • Further our understanding of SYNGAP1 biology
  • Researchers: Interested? Please submit a proposal to SRF by March 1 or September 1 for SAB review.

Learn more…

Learn more about missense mutations in Episode 44 of Syngap10, SRF’s weekly briefing on everything you need to know about SYNGAP1.

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