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