Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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. |
| Labcorp Genetics |
RCV000083929 | SCV000826109 | uncertain significance | TNF receptor-associated periodic fever syndrome (TRAPS) | 2023-08-22 | criteria provided, single submitter | clinical testing | 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: 21420073). ClinVar contains an entry for this variant (Variation ID: 97676). This missense change has been observed in individuals with clinical features of TNFRSF1A-related conditions (PMID: 21420073, 23965844; Invitae). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the TNFRSF1A protein (p.Phe89Leu). This variant is not present in population databases (gnomAD no frequency). 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, |
RCV000083929 | SCV000116041 | not provided | TNF receptor-associated periodic fever syndrome (TRAPS) | no assertion provided | not provided |