ClinVar Miner

Submissions for variant NM_001065.3(TNFRSF1A):c.282C>G (p.Asn94Lys) (rs876661014)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218061 SCV000279191 likely pathogenic not provided 2016-05-23 criteria provided, single submitter clinical testing The N94K variant has been published in a patient diagnosed with TRAPS (Kirresh et al., 2016). The N94K 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. The N94K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Another variant at this position, N94I aka N65I, has been reported in association with TRAPS (Aganna et al., 2003). Therefore, based on the currently available information, this variant is likely pathogenic.
Invitae RCV000699281 SCV000827985 uncertain significance TNF receptor-associated periodic fever syndrome (TRAPS) 2018-11-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 94 of the TNFRSF1A protein (p.Asn94Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TNFRSF1A-related disease. ClinVar contains an entry for this variant (Variation ID: 234421). 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 and their clinical significance is uncertain. 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.

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