ClinVar Genomic variation as it relates to human health
NM_001065.4(TNFRSF1A):c.123T>G (p.Asp41Glu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(3); Likely pathogenic(8); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001065.4(TNFRSF1A):c.123T>G (p.Asp41Glu)
Variation ID: 97643 Accession: VCV000097643.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6334161 (GRCh38) [ NCBI UCSC ] 12: 6443327 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2014 Apr 15, 2024 Nov 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001065.4:c.123T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001056.1:p.Asp41Glu missense NM_001346091.2:c.-131-296T>G intron variant NM_001346092.2:c.-455T>G 5 prime UTR NR_144351.2:n.385T>G non-coding transcript variant NC_000012.12:g.6334161A>C NC_000012.11:g.6443327A>C NG_007506.1:g.12935T>G LRG_193:g.12935T>G LRG_193t1:c.123T>G LRG_193p1:p.Asp41Glu - Protein change
- D41E
- Other names
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- Canonical SPDI
- NC_000012.12:6334160:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TNFRSF1A | - | - |
GRCh38 GRCh37 |
518 | 588 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Nov 17, 2023 | RCV000083896.22 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Apr 1, 2023 | RCV000255687.34 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 29, 2016 | RCV000623098.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 8, 2021 | RCV002262667.10 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Dec 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061754.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 05, 2022 |
Comment:
PM2
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Likely pathogenic
(Feb 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512280.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 moderate, PM6, PP1 moderate, PP4 supporting
Geographic origin: Brazil
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002519880.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
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Likely pathogenic
(Aug 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543084.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Likely pathogenic
(Apr 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741504.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
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Likely pathogenic
(Dec 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321967.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
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: … (more)
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) (less)
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Pathogenic
(Aug 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915604.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Apr 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049603.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Oct 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580374.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM2_SUP, PP1, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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TNF receptor-associated periodic fever syndrome (TRAPS)
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768938.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
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Likely pathogenic
(Nov 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001235309.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Apr 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247007.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
TNFRSF1A: PP1:Strong, PM2:Supporting, PS3:Supporting
Number of individuals with the variant: 3
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978548.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931593.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974938.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: yes
Allele origin:
unknown
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Genomics And Bioinformatics Analysis Resource, Columbia University
Accession: SCV004024144.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023
Comment:
heterozygous
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not provided
(-)
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no classification provided
Method: not provided
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TNF receptor-associated periodic fever syndrome (TRAPS)
Affected status: not provided
Allele origin:
not provided
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Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Accession: SCV000116002.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations. | Similuk MN | The Journal of allergy and clinical immunology | 2022 | PMID: 35753512 |
Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF-α Receptor-Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network. | Gaggiano C | Mediators of inflammation | 2020 | PMID: 32831641 |
Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives. | Cudrici C | International journal of molecular sciences | 2020 | PMID: 32380704 |
Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome. | Pucino V | Journal of leukocyte biology | 2016 | PMID: 26598380 |
The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. | Cantarini L | Seminars in arthritis and rheumatism | 2014 | PMID: 24393624 |
The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. | Lachmann HJ | Annals of the rheumatic diseases | 2014 | PMID: 23965844 |
Expanding spectrum of TNFRSF1A gene mutations among patients with idiopathic recurrent acute pericarditis. | Cantarini L | Internal medicine journal | 2013 | PMID: 23745996 |
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. | Havla J | The Journal of rheumatology | 2013 | PMID: 23322460 |
Tumour necrosis factor receptor-associated periodic syndrome caused by a rare mutation in the TNFRSF1A gene, and with excellent response to etanercept treatment. | Cantarini L | Clinical and experimental rheumatology | 2009 | PMID: 19917181 |
A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. | Gattorno M | Arthritis and rheumatism | 2008 | PMID: 18512793 |
Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis: pathogenetic and clinical implications. | D'Osualdo A | Arthritis and rheumatism | 2006 | PMID: 16508982 |
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Text-mined citations for rs104895271 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.