Submission Details

TNFRSF1A was first reported in relation to autosomal dominant TNFR1-associated periodic syndrome (TRAPS) in 1999 (McDermott et al., PMID: 10199409). TRAPS is characterized by episodes of symptoms including fever, abdominal pain, arthralgia, myalgia, migratory rash, and eye inflammation. Flares often occur every 4-6 weeks and last for 5-25 days, which is much longer than many other autoinflammatory disorders. Flare symptoms, frequency and duration may be highly variable. Patients often respond to Interleukin-1 (IL-1) inhibitors. 13 variants that have been reported in 25 probands in 10 publications (PMIDs: 21173015, 15570662, 15216558, 11239851, 38155741, 38978873, 33715002, 10199409, 12595616, 31562507) are included in this curation. The variants are all missense variants impacting cystine residues, which are known to be important for protein folding, with the exception of Thr79Met. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. TRAPS variants appear to be gain-of-function. Several TNFRSF1A variants have been shown to lead to defective receptor shedding, which ultimately results in increased cytokine activity and upregulated TNFR1 signaling. These studies have been completed in both human cells and in mice (10199409, 25888769). In summary, there is definitive evidence supporting the relationship between TNFRSF1A and autosomal dominant TNFR1-associated periodic syndrome (TRAPS). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Monogenic Autoinflammatory GCEP on April 21st, 2025 (SOP Version 10).