Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000083905 | SCV000637234 | uncertain significance | TNF receptor-associated periodic fever syndrome (TRAPS) | 2017-03-27 | criteria provided, single submitter | clinical testing | This variant affects a cysteine residue located in the extracellular domain of the TNFRSF1A protein. Cysteine residues in this domain of TNFRSF1A are involved in the formation of disulfide bridges critical for subcellular protein trafficking (PMID: 27332769, 16684962). In addition, missense substitutions within the TNFRSF1A extracellular domain affecting cysteine residues are overrepresented in patients with periodic fever compared to the general population (gnomAD). In summary, this variant is absent in the population and has been observed in at least one affected individual. In addition, it is predicted to disrupt protein function. However, additional genetic or functional data are needed to further assess the clinical impact of this variant. For these reasons, this change has been classified as a Variant of Uncertain Significance. A different missense substitution at this codon (p.Cys59Arg) has been determined to be pathogenic (PMID: 23965844, Invitae). This suggests that the cysteine residue is critical for TNFRSF1A protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in the literature for at least one individual affected with TNF receptor-associated autoinflammatory syndrome (PMID: 15216558, 23965844). ClinVar contains an entry for this variant (Variation ID: 97652). This variant is also known as p.Cys30Tyr in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 59 of the TNFRSF1A protein (p.Cys59Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. |
| Mayo Clinic Laboratories, |
RCV004791264 | SCV005414060 | likely pathogenic | not provided | 2023-09-14 | criteria provided, single submitter | clinical testing | PP3, PM1, PM2, PM5, PS4_moderate |
| Unité médicale des maladies autoinflammatoires, |
RCV000083905 | SCV000116012 | not provided | TNF receptor-associated periodic fever syndrome (TRAPS) | no assertion provided | not provided |