ClinVar Genomic variation as it relates to human health

The C59R missense variant in the TNFRSF1A gene has been reported previously in association with TRAPS (McDermott et al., 1999; Jesus et al., 2012). The variant is not observed in large population cohorts (Lek et al., 2016). C59R 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The variant occurs at a conserved position in a cysteine-rich domain of the extracellular region of the TNFRSF1A protein. Loss of this cysteine residue is expected to disrupt disulfide bond formation, and C59R has been shown to result in abnormal localization of the protein in the cell (Lobito et al., 2006). Missense variants in the same (C59F/Y/S) and nearby residues (C58R/Y/F, C62G/Y) have been reported in the Human Gene Mutation Database in association with TRAPS (Stenson et al., 2014). In summary, we consider this variant to be pathogenic.

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 59 of the TNFRSF1A protein (p.Cys59Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TNF receptor-associated periodic fever syndrome (TRAPS) (PMID: 10199409, 11722598, 22566169, 23965844). It has also been observed to segregate with disease in related individuals. This variant is also known as C30R. ClinVar contains an entry for this variant (Variation ID: 12337). 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: 16684962). This variant disrupts the p.Cys59 amino acid residue in TNFRSF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1144354, 10902757, 20576331). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

Variant interpreted as Pathogenic and reported on 12-08-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.