ClinVar Miner

Submissions for variant NM_001065.3(TNFRSF1A):c.265T>C (p.Phe89Leu) (rs104895245)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254771 SCV000321968 likely pathogenic not provided 2016-08-01 criteria provided, single submitter clinical testing The F89L variant has been published previously in association with TRAPS (Lachmann et al., 2014). Additionally, other publications have reported this variant as F60L, arising from both a c.264 C>G and a c.267 A>G nucleotide change (Aganna et al., 2003; Dinc et al., 2005). While these papers may be reporting the same F60L variant caused by separate nucleotide changes, they did not include information necessary for us to determine the cause of these nomenclature discrepancies. The 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. F89L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved; however, in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that F89L increases TNF-stimulated c-Rel activity (Nedjai et al., 2011). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000083929 SCV000826109 uncertain significance TNF receptor-associated periodic fever syndrome (TRAPS) 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 89 of the TNFRSF1A protein (p.Phe89Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with TRAPS (PMID: 23965844, Invitae). In addition, a different nucleotide change c.267C>G resulting in the same amino acid change has been reported in a family affected with TRAPS (PMID: 21420073). This variant is also known as p.Phe60Leu or F60L in the literature. ClinVar contains an entry for this variant (Variation ID: 97676). Experimental studies have shown that this missense change results in elevated TNF-stimulated c-Rel activity (PMID: 21420073). The observation of one or more missense substitutions at this codon (p.Phe89Leu, p.Phe89Val) in affected individuals suggests that this may be a clinically significant residue (PMID: 16401480). 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.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000083929 SCV000116041 not provided TNF receptor-associated periodic fever syndrome (TRAPS) no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.