Submissions for variant NM_001065.4(TNFRSF1A):c.123T>G (p.Asp41Glu)

dbSNP: rs104895271

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255687	SCV000321967	likely pathogenic	not provided	2021-12-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(D12E); This variant is associated with the following publications: (PMID: 32565720, 24393624, 23965844, 16508982, 18512793, 25637003, 27068928, 26821543, 26299986, 29062244, 32199921, 32831641, 26992170, 26965498, 31589614, 26598380, 19917181, 23322460, 23745996, 34426522)
Ambry Genetics	RCV000623098	SCV000741504	likely pathogenic	Inborn genetic diseases	2016-04-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000083896	SCV000915604	pathogenic	TNF receptor-associated periodic fever syndrome (TRAPS)	2018-08-15	criteria provided, single submitter	clinical testing	The TNFRSF1A c.123T>G (p.Asp41Glu) missense variant, also known as D12E, has been reported in at least four studies in which it is found in a heterozygous state in at least nine individuals with familial periodic fever (FPF) with widely variable symptoms (D'Osualdo et al. 2006; Cantarini et al. 2009; Cantarini et al. 2013; Havla et al. 2013; Lachmann et al. 2014). In two of these affected individuals, the p.Asp41Glu variant was not detected in the parents and is reported as de novo (Cantarini et al. 2009; Cantarini et al. 2013) while Havla et al. (2013), report two unrelated probands with a family history of FPF-related symptoms. An additional individual with a clinical history of periodic fever was reported to carry the p.Asp41Glu variant in the heterozygous state and a missense variant in the MEFV gene in the homozygous status, and was diagnosed with familial Mediterranean fever, highlighting the extensive overlap in clinical manifestations between these two conditions (Gattorno et al. 2008). Of note, not all known genes associated with periodic fever were assessed in these affected individuals. Control data are unavailable for this variant, which is reported at a frequency of 0.00033 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Asp41Glu variant is classified as likely pathogenic for familial periodic fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000083896	SCV001235309	likely pathogenic	TNF receptor-associated periodic fever syndrome (TRAPS)	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 41 of the TNFRSF1A protein (p.Asp41Glu). This variant is present in population databases (rs104895271, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with TNF receptor-associated periodic fever syndrome (TRAPS) (PMID: 16508982, 23322460, 24393624, 35753512). It has also been observed to segregate with disease in related individuals. This variant is also known as D12E. ClinVar contains an entry for this variant (Variation ID: 97643). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TNFRSF1A protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNFRSF1A function (PMID: 26598380). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000255687	SCV001247007	likely pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	TNFRSF1A: PP1:Strong, PM2:Supporting, PS3:Supporting
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255687	SCV002049603	likely pathogenic	not provided	2021-04-02	criteria provided, single submitter	clinical testing	The TNFRSF1A c.123T>G; p.Asp41Glu variant (rs104895271), also published as D12E, is reported in the literature in several individuals affected with periodic fever or inflammatory syndromes (Bozgeyik 2020, Cantarini 2014, D'Osualdo 2006, Lachmann 2014). The variant is reported to segregate with disease in one family (Havla 2013) and developed de novo in another affected individual (Cantarini 2013). The variant is reported in the ClinVar database (Variation ID: 97643) and is listed in the European (non-Finnish) population with an allele frequency of 0.03% (41/128,538 alleles) in the Genome Aggregation Database. The aspartic acid at codon 41 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.541). Based on available information, this variant is considered to be likely pathogenic, but is associated with a mild phenotype and low penetrance. References: Bozgeyik E et al. Next-generation screening of a panel of genes associated with periodic fever syndromes in patients with Familial Mediterranean Fever and their clinical characteristics. Genomics. 2020 Jul;112(4):2755-2762. Cantarini L et al. The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. Semin Arthritis Rheum. 2014 Jun;43(6):818-23. Cantarini L et al. Expanding spectrum of TNFRSF1A gene mutations among patients with idiopathic recurrent acute pericarditis. Intern Med J. 2013 Jun;43(6):725-7. 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. Havla J et al. Symptoms related to tumor necrosis factor receptor 1-associated periodic syndrome, multiple sclerosis, and severe rheumatoid arthritis in patients carrying the TNF receptor superfamily 1A D12E/p.Asp41Glu mutation. J Rheumatol. 2013 Mar;40(3):261-4. 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 Dec;73(12):2160-7. 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000255687	SCV002061754	uncertain significance	not provided	2021-12-06	criteria provided, single submitter	clinical testing	PM2
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000083896	SCV002512280	likely pathogenic	TNF receptor-associated periodic fever syndrome (TRAPS)	2021-02-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 moderate, PM6, PP1 moderate, PP4 supporting
Mendelics	RCV000083896	SCV002519880	pathogenic	TNF receptor-associated periodic fever syndrome (TRAPS)	2022-05-04	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262667	SCV002543084	likely pathogenic	Autoinflammatory syndrome	2021-08-08	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000083896	SCV002580374	likely pathogenic	TNF receptor-associated periodic fever syndrome (TRAPS)	2021-10-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000083896	SCV002768938	pathogenic	TNF receptor-associated periodic fever syndrome (TRAPS)	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Missense variants have been demonstrated to increase STAT-mTOR signalling (PMID: 26598380), however, as this protein homotrimerizes dominant negative is also a potential mechanism (PMID: 32380704). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Missense variants that do not impact a cysteine residue are well known to have incomplete penetrance (PMID: 32831641, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (44 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and observed in multiple individuals or families with familial periodic fever, idiopathic recurrent acute pericarditis or TNF-receptor-associated periodic syndrome (TRAPS). In one of these individuals, segregation testing proved the variant was de novo (ClinVar, PMID: 23322460, PMID: 32831641, PMID: 23745996). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083896	SCV000116002	not provided	TNF receptor-associated periodic fever syndrome (TRAPS)		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255687	SCV001931593	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255687	SCV001974938	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255687	SCV001978548	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000083896	SCV004024144	likely pathogenic	TNF receptor-associated periodic fever syndrome (TRAPS)		no assertion criteria provided	research