ClinVar Miner

Submissions for variant NM_001065.3(TNFRSF1A):c.596T>C (p.Ile199Thr) (rs104895247)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219058 SCV000279197 uncertain significance not provided 2015-03-20 criteria provided, single submitter clinical testing The I199T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I199T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A missense mutation at this residue (I199N) has been reported in the Human Gene Mutation Database in association with periodic fever syndromes (Stenson et al., 2009), supporting the functional importance of this region of the protein. The I199T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV001068583 SCV001233704 uncertain significance TNF receptor-associated periodic fever syndrome (TRAPS) 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 199 of the TNFRSF1A protein (p.Ile199Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs104895247, ExAC 0.008%). This variant has not been reported in the literature in individuals with TNFRSF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 234423). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000219058 SCV001246266 uncertain significance not provided 2019-09-01 criteria provided, single submitter clinical testing
Department of Immunology,Hospital Universitario Virgen del Rocio RCV000495530 SCV000580675 pathogenic Behcet's syndrome 2017-06-25 no assertion criteria provided case-control

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