TNFRSF1A

Inheritance Pattern: AD

Disease ID:MONDO:0007727

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0007727

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007727

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0007727

Submitter: Illumina

The TNFRSF1A gene is located on chromosome 12 at 12p13.31 and encodes the TNF receptor superfamily member 1A protein, which is one of two membrane receptors bound by the proinflammatory cytokine TNF. TNFRSF1A was first reported in relation to familial periodic fever in 1999 (10199409: McDermott et al. 1999). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 19 unique missense variants have been reported in 20 cases from eight publications (10199409: McDermott et al. 1999; 10902757: Dode et al. 2000; 13130484: Aganna et al. 2003; 16508982: D'Osualdo et al. 2006; 22566169: Jesus et al. 2012; 23322460: Havla et al. 2013; 22343913: Lee et al. 2013; 25888769: Greco et al. 2015). More evidence is available in the literature, but the maximum score for probands with other variant type with some evidence of gene impact (7 pts) has been reached. This gene-disease relationship is supported by the biochemical function of TNFR1 signaling via two opposing pathways that lead to either apoptosis via caspase activation or to cellular survival and inflammation via the activation of NF-κB, functional alteration in patient and non-patient cells demonstrating reduced soluble TNFR1 impaired binding and intracellular signaling downstream of TNFR1, resulting in enhanced production of cytokines and chemokines (17666110: Kimberley et al. 2007; 16684962: Lobito et al. 2006; 20457915: Simon et al. 2010). In two different knock-in mouse lines with TRAPS-associated variants in TNFRSF1A, TNFR1 accumulated intracellularly and there was enhanced activation of proinflammatory signaling. Heterozygous mice were hypersensitive to lipopolysaccharide (LPS), an endotoxin, which was also observed in TRAPS patient cells (20457915: Simon et al. 2010). In summary, TNFRSF1A is definitively associated with familial periodic fever. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0007727

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0007727

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0007727

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0007727

Submitter: ClinGen

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).