ClinVar Miner

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

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Total submissions: 6
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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 RCV000084193 SCV000356964 likely benign Familial cold urticaria 2017-04-27 criteria provided, single submitter clinical testing 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV001085335 SCV000646263 likely benign Cryopyrin associated periodic syndrome 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000223458 SCV001147801 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000468 SCV001157330 uncertain significance not specified 2018-12-02 criteria provided, single submitter clinical testing The NLRP3 c.1469G>A; p.Arg490Lys variant (rs145268073), also known as Arg488Lys, is published in the medical literature in several individuals with cryopyrin-associated periodic syndrome (CAPS) as well as unaffected family members (Arostegui 2004, Haverkamp 2014, Kuemmerle-Deschner 2017, Rae 2018, Rowczenio 2013). The variant has been implicated as a low penetrance variant that shows variable expressivity (Kuemmerle-Deschner 2017, Rowczenio 2013). The variant is listed in the ClinVar database (Variation ID: 97934) and in the general population with an allele frequency of 0.07% (188/281098 alleles) in the Genome Aggregation Database. The arginine at this position is conserved but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Arostegui JI et al. Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene. Arthritis Rheum. 2004 Dec;50(12):4045-50. Haverkamp MH et al. Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS). Clin Exp Immunol. 2014 Sep;177(3):720-31. Kuemmerle-Deschner JB et al. Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges. Arthritis Rheumatol. 2017 Nov;69(11):2233-2240. Rae W et al. Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics. Clin Genet. 2018 Mar;93(3):647-655. Rowczenio DM et al. Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature. Arthritis Res Ther. 2013 Feb 19;15(1):R30.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084193 SCV000116326 not provided Familial cold urticaria no assertion provided not provided

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