TNFRSF1A

Genetic findings for TNFRSF1A in TNF Receptor-Associated Periodic Syndrome

Variants (4)

Variant	Type	Frequency	Significance
Cysteine-disrupting mutations (multiple)	germline	~27% of Eurofever patients	High-penetrance pathogenic variants. Disrupt disulfide bonds in CRD1/CRD2 of the TNFR1 extracellular domain. Associated with severe phenotype and high amyloidosis risk (24% vs 2% for non-cysteine).
T50M (p.Thr79Met)	germline	~10% of Eurofever patients	Most common high-penetrance pathogenic variant. Affects a conserved hydrogen bond critical for protein folding in CRD1. Despite not disrupting a cysteine, carries high disease penetrance and amyloidosis risk similar to cysteine mutations.
R92Q (p.Arg121Gln)	germline	~34% of Eurofever patients (most common variant overall)	Low-penetrance variant of uncertain pathogenic significance. Present in 1.2–4% of healthy Caucasians. Associated with milder disease, shorter episodes, less familial aggregation (19% vs 64%), and higher spontaneous resolution rates. Classified as INSAID Group B (uncertain significance).
P46L (p.Pro75Leu)	germline	Low-penetrance, uncertain pathogenicity	Another low-penetrance variant. Found at high frequency in sub-Saharan West African populations. Clinical significance debated — may be a benign polymorphism in some ethnic backgrounds.

Clinical implications

Cysteine-disrupting mutations (multiple)

Aggressive treatment with IL-1 blockade recommended. Intensive SAA monitoring for amyloidosis. Higher penetrance (93%).

T50M (p.Thr79Met)

Classified as pathogenic (INSAID Group A). Requires biologic treatment and amyloidosis surveillance.

R92Q (p.Arg121Gln)

Diagnosis of TRAPS should be made cautiously. Colchicine or NSAIDs may suffice. Amyloidosis risk is very low. Some cases may represent coincidental finding.

Also found in: Multiple sclerosis (Occasional co-occurrence reported)

P46L (p.Pro75Leu)

Context-dependent interpretation required. May be benign in African populations where allele frequency is high.

Related molecules

TNFR1 (TNFRSF1A)established

Mutated receptor — primary disease gene product — Misfolded / ER-retained

Sources (12)

DetailsAksentijevich I et al. (2001) The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers · Am J Hum GenetDOI ↗

DetailsHull KM et al. (2002) The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder · Medicine (Baltimore)DOI ↗

DetailsLachmann HJ et al. (2014) The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry · Ann Rheum DisDOI ↗

DetailsMcDermott MF et al. (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes · CellDOI ↗

DetailsPapa R et al. (2021) INSAID variant classification and Eurofever criteria guide optimal treatment strategy in patients with TRAPS: data from the Eurofever Registry · J Allergy Clin Immunol PractDOI ↗

DetailsPelagatti MA et al. (2011) Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene · Arthritis RheumDOI ↗

DetailsRuiz-Ortiz E et al. (2017) Disease phenotype and outcome depending on age at disease onset in patients carrying the R92Q low-penetrance variant in TNFRSF1A gene · Front ImmunolDOI ↗

DetailsCudrici C et al. (2020) Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives · Int J Mol SciDOI ↗

DetailsHull KM et al. (2002) The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder · Medicine (Baltimore)DOI ↗