ClinVar Genomic variation as it relates to human health

The TNFRSF1A c.269C>T; p.Thr90Ile variant, also known as Thr61Ile, is published in the medical literature in several individuals with suspected TRAPS (Ida 2004, Ohmori 2014, Ueda 2016), but has also been published at a similar frequency in control individuals from the same ethnic group (Ida 2004, Ueda 2016). The variant is not listed in the ClinVar database, but is listed in the dbSNP variant database (rs34751757). The variant is described in the Genome Aggregation Database in 0.1 percent (20/13848 alleles) of the East Asian population. The threonine at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Additionally, another variant in the same amino acid, p.Thr90Pro, is published in an individual with suspected TRAPS and the variant appeared to segregate with disease. However, due to conflicting information, this variant cannot be classified with certainty. Pathogenic TNFRSF1A variants are associated with autosomal dominant periodic fever (MIM#142680). References: Ida H et al. A novel mutation (T61I) in the gene encoding tumour necrosis factor receptor superfamily 1A (TNFRSF1A) in a Japanese patient with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) associated with systemic lupus erythematosus. Rheumatology (Oxford). 2004 Oct;43(10):1292-9. Ohmori S et al. Inflammatory response to heparinoid and heparin in a patient with tumor necrosis factor receptor-associated periodic syndrome: the second case with a T61I mutation in the TNFRSF1A gene. J Dermatol. 2014 Dec;41(12):1112-3. Ueda N et al. Clinical and Genetic Features of Patients With TNFRSF1A Variants in Japan: Findings of a Nationwide Survey. Arthritis Rheumatol. 2016 Nov;68(11):2760-2771. Radhakrishna SM et al. Novel mutation identified in severe early-onset tumor necrosis factor receptor-associated periodic syndrome: a case report. BMC Pediatr. 2017 Apr 20;17(1):108.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: TNFRSF1A c.269C>T (p.Thr90Ile) results in a non-conservative amino acid change located in the TNFR/NGFR cysteine-rich region (IPR001368) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 1583076 control chromosomes, predominantly at a frequency of 0.0067 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF1A causing TNF Receptor-Associated Periodic Fever Syndrome phenotype. c.269C>T has been reported in the literature in individuals affected with TNF Receptor-Associated Periodic Fever Syndrome as well as unaffected individuals (examples: Ida_2004 and Ueda_2016). These report(s) do not provide unequivocal conclusions about association of the variant with TNF Receptor-Associated Periodic Fever Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Ueda_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27332769, 15280569). ClinVar contains an entry for this variant (Variation ID: 532185). Based on the evidence outlined above, the variant was classified as likely benign.