ClinVar Genomic variation as it relates to human health
NM_001065.4(TNFRSF1A):c.236C>T (p.Thr79Met)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001065.4(TNFRSF1A):c.236C>T (p.Thr79Met)
Variation ID: 12336 Accession: VCV000012336.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.31 12: 6333823 (GRCh38) [ NCBI UCSC ] 12: 6442989 (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 Apr 4, 2013 Apr 15, 2024 Nov 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001065.4:c.236C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001056.1:p.Thr79Met missense NM_001346091.2:c.-89C>T 5 prime UTR NM_001346092.2:c.-342C>T 5 prime UTR NR_144351.2:n.498C>T non-coding transcript variant NC_000012.12:g.6333823G>A NC_000012.11:g.6442989G>A NG_007506.1:g.13273C>T LRG_193:g.13273C>T LRG_193t1:c.236C>T LRG_193p1:p.Thr79Met P19438:p.Thr79Met - Protein change
- T79M
- Other names
- T50M
- Canonical SPDI
- NC_000012.12:6333822:G:A
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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
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The frequency of the allele represented by this VCV record.
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
517 | 587 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2023 | RCV000013129.36 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2023 | RCV000414218.17 |
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
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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
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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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Pathogenic
(Oct 04, 2020)
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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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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001448272.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Sex: male
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Pathogenic
(Dec 23, 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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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002072464.1
First in ClinVar: Feb 02, 2022 Last updated: Feb 02, 2022 |
Sex: female
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Pathogenic
(Jan 14, 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: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761858.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Jan 03, 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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GeneDx
Accession: SCV000490856.3
First in ClinVar: Jan 09, 2017 Last updated: Jan 15, 2023 |
Comment:
Published functional studies demonstrate a damaging effect due to cytoplasmic retention, reduced protein surface expression, impaired binding of TNF-alpha, and activation of the TNF-R1 and … (more)
Published functional studies demonstrate a damaging effect due to cytoplasmic retention, reduced protein surface expression, impaired binding of TNF-alpha, and activation of the TNF-R1 and inflammasome pathways (Todd et al., 2004; Greco et al., 2015).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(T50M); This variant is associated with the following publications: (PMID: 24950168, 25888769, 24393624, 26598380, 21153350, 16684962, 15312137, 21282379, 23894535, 20457915, 10199409, 25936627, 27332769, 33440462, 11722598, 31586650, 33284430, 31562507, 35577052, 15570662, 23965844) (less)
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Pathogenic
(Nov 04, 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: SCV000958864.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 79 of the TNFRSF1A protein (p.Thr79Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 79 of the TNFRSF1A protein (p.Thr79Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TNF receptor-associated periodic fever syndrome (PMID: 10199409, 13130484, 23965844, 24393624, 25936627). It has also been observed to segregate with disease in related individuals. This variant is also known as T50M. ClinVar contains an entry for this variant (Variation ID: 12336). 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) has been performed at Invitae 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: 15312137, 20457915). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961330.14
First in ClinVar: Oct 08, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 02, 1999)
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no assertion criteria provided
Method: literature only
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PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033376.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 24, 2020 |
Comment on evidence:
In 8 of 8 affected members of an Irish family from the familial Hibernian fever (142680) linkage study (McDermott et al., 1998), McDermott et al. … (more)
In 8 of 8 affected members of an Irish family from the familial Hibernian fever (142680) linkage study (McDermott et al., 1998), McDermott et al. (1999) identified a mutation in the TNFRSF1A gene, leading to the substitution of methionine for threonine at residue 50. Two additional members of this family who had mild symptoms proved also to have this mutation. The 1 available member of a French-Canadian family had the same mutation. (less)
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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: SCV000116031.1
First in ClinVar: Mar 06, 2014 Last updated: Mar 06, 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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Adult-onset tumour necrosis factor receptor-associated periodic syndrome presenting with refractory chronic arthritis. | Lopalco G | Clinical and experimental rheumatology | 2015 | PMID: 25936627 |
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 |
Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. | Simon A | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20457915 |
Mutant forms of tumour necrosis factor receptor I that occur in TNF-receptor-associated periodic syndrome retain signalling functions but show abnormal behaviour. | Todd I | Immunology | 2004 | PMID: 15312137 |
Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. | Aganna E | Arthritis and rheumatism | 2003 | PMID: 13130484 |
Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. | McDermott MF | Cell | 1999 | PMID: 10199409 |
Linkage of familial Hibernian fever to chromosome 12p13. | McDermott MF | American journal of human genetics | 1998 | PMID: 9585614 |
Text-mined citations for rs104895219 ...
HelpRecord last updated Apr 15, 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.