ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.1469G>A (p.Arg490Lys) (rs145268073)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223458 SCV000278946 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing The R490K variant in the NLRP3 gene has been reported in the heterozygous state, sometimes as R488K, in non-CAPS (cryopyrin-associated periodic syndromes) individuals with atypical inflammatory symptoms, and in an individual with familial cold autoinflammatory syndrome (FCAS), however heterozygous unaffected family members were also detected (Arostegui et al., 2004; Aksentijevich et al., 2007; Haverkamp et al., 2014). As compared with individuals with other pathogenic variants in the NLRP3 gene, individuals with the R490K variant or another low-penetrance variant" were reported to have an increased frequency of fever and gastrointestinal symptoms and a decreased frequency of eye disease, hearing loss, and renal involvement (Kuemmerle-Deschner et al., 2017). The R490K variant has also been reported in the compound heterozygous state with another NLRP3 variant in an individual with a diagnosis of Muckle Wells syndrome (Torres et al., 2018). The R490K variant is observed in 157/126,472 (0.12%) alleles from individuals of non-Finnish European background and 186/275,688 total alleles, in large population cohorts (Lek et al., 2016). This substitution occurs within the NACHT domain, which is a critical functional domain (Masters et al., 2009). However, the R490K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. We interpret R490K as a variant of uncertain significance."
Illumina Clinical Services Laboratory,Illumina RCV000360373 SCV000356964 likely benign Familial cold autoinflammatory syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000538256 SCV000646263 likely benign Cryopyrin associated periodic syndrome 2017-07-24 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084193 SCV000116326 not provided Familial cold urticaria no assertion provided not provided

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