ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.784C>T (p.Arg262Trp) (rs121908150)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000221297 SCV000278937 pathogenic not provided 2018-06-27 criteria provided, single submitter clinical testing The R262W missense variant in the NLRP3 gene has been reported previously in association withboth Muckle-Wells and Familial Cold Autoinflammatory syndromes (Dode et al., 2002; Leslie et al.,2006; Lepore et al., 2010; Parker et al., 2016). Carriers of the R262W variant, reported as R260W,have also presented with the additional symptoms of sensorineural hearing loss and vision impairment(Alejandre et al., 2014). R262W was observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. It is a non-conservative amino acid substitution, which is likely toimpact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position that is conserved across species and in silico analysispredicts this variant is probably damaging to the protein structure/function. In addition, missensevariants at the same (R262P) and in nearby residues (C261W, V264A, V264G, L266F/V, L266R/H)have been reported in the Human Gene Mutation Database in association with NLRP3-relateddisorders (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV001067187 SCV001232233 pathogenic Cryopyrin associated periodic syndrome 2019-03-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 262 of the NLRP3 protein (p.Arg262Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with cryopyrin-associated periodic syndromes (CAPS) in several families (PMID: 11992256, 20472245). In the literature, this variant is also known as R260W and the NLRP3 gene is also known as CIAS1. ClinVar contains an entry for this variant (Variation ID: 4374). This variant (or the murine equivalent of this variant, known as R258W) has been reported to affect NLRP3 protein function (PMID: 23703389, 15020601). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004622 SCV000024796 pathogenic Familial amyloid nephropathy with urticaria AND deafness 2002-06-01 no assertion criteria provided literature only
OMIM RCV000004623 SCV000024797 pathogenic Familial cold urticaria 2002-06-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000004623 SCV000116365 not provided Familial cold urticaria no assertion provided not provided

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