ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223458 SCV000278946 uncertain significance not provided 2021-05-18 criteria provided, single submitter clinical testing 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). Heterozygous unaffected family members were also detected (Arostegui et al., 2004; Aksentijevich et al., 2007; Haverkamp et al., 2014).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33207704, 26984802, 24773462, 17393462, 15593220, 29922587, 29077208, 28692792, 32707200, 33329557)
Illumina Clinical Services Laboratory,Illumina RCV000084193 SCV000356964 likely benign Familial cold autoinflammatory syndrome 1 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 2020-11-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000223458 SCV001147801 uncertain significance not provided 2020-07-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000468 SCV001157330 uncertain significance none provided 2020-03-06 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.
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375155 SCV001572113 benign Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing BS1_Strong, BS2_Strong, BP4_Supporting
Mayo Clinic Laboratories, Mayo Clinic RCV000223458 SCV001715677 uncertain significance not provided 2020-08-13 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084193 SCV000116326 not provided Familial cold autoinflammatory syndrome 1 no assertion provided not provided

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