Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001002161 | SCV001160018 | pathogenic | not specified | 2018-10-16 | criteria provided, single submitter | clinical testing | The TNFRSF1A c.251G>A; p.Cys84Tyr variant (rs104895224), also known as Cys55Tyr or C55Y, has been published in the medical literature in several individuals with high penetrance TRAPS (D'Osulado 2006, Lachmann 2014, Papa 2017, Pelagatti 2011). Additionally, other variants in this codon (p.Cys84Arg, p.Cys84Ser) have been described in individuals with TRAPS (Rudofsky 2006, Jadoul 2001). The c.251G>A; p.Cys84Tyr variant has been described as a validated pathogenic variant by an expert group (see link to database below) and has also been described in the ClinVar database (Variation ID: 97673). The variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 84 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. The cysteine at this position is part of a cysteine-rich domain and is in the ligand-binding domain (Rebelo 2006). Functional analyses show this variant alters phenotype (Bachetti 2013, Pucino 2016). Considering available information, this variant is classified as pathogenic. References: Link to TNFRSF1A Infevers database: https://infevers.umai-montpellier.fr/web/search.php?n=2 Bachetti T et al. Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann Rheum Dis. 2013 Jun;72(6):1044-52. D'Osualdo A et al. Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications. Arthritis Rheum. 2006 Mar;54(3):998-1008. Jadoul M et al. Autosomal-dominant periodic fever with AA amyloidosis: Novel mutation in tumor necrosis factor receptor 1 gene Rapid Communication. Kidney Int. 2001 May;59(5):1677-82. Lachmann HJ et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014;73:2160-2167 Papa R et al. A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet J Rare Dis. 2017 Oct 18;12(1):167. Pelagatti MA et al. Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene. Arthritis Rheum. 2011 Apr;63(4):1141-50. Pucino V et al. Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome. J Leukoc Biol. 2016 May;99(5):761-9. Rebelo SL et al. Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function. Arthritis Rheum. 2006 Aug;54(8):2674-87. Rudofsky G Jr et al. A nephrotic patient with tumour necrosis factor receptor-associated periodic syndrome, IgA nephropathy and CNS involvement. Nephrol Dial Transplant. 2006 Apr;21(4):1109-12. |
| Labcorp Genetics |
RCV000083926 | SCV001565013 | likely pathogenic | TNF receptor-associated periodic fever syndrome (TRAPS) | 2024-10-20 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 84 of the TNFRSF1A protein (p.Cys84Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tumor necrosis factor receptor-associated periodic fever syndrome (PMID: 16508982, 23965844; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys55Tyr. ClinVar contains an entry for this variant (Variation ID: 97673). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNFRSF1A protein function. Experimental studies have shown that this missense change affects TNFRSF1A function (PMID: 23117241). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Eurofins- |
RCV000083926 | SCV003935082 | pathogenic | TNF receptor-associated periodic fever syndrome (TRAPS) | 2022-10-26 | criteria provided, single submitter | clinical testing | |
| Unité médicale des maladies autoinflammatoires, |
RCV000083926 | SCV000116038 | not provided | TNF receptor-associated periodic fever syndrome (TRAPS) | no assertion provided | not provided |