Submissions for variant NM_001243133.2(NLRP3):c.1463G>A (p.Arg488Lys)

gnomAD frequency: 0.00070  dbSNP: rs145268073

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223458	SCV000278946	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	Reported in the heterozygous state 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 (PMID: 15593220, 17393462, 24773462); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(R488K); This variant is associated with the following publications: (PMID: 26984802, 24773462, 17393462, 29922587, 29077208, 28692792, 33329557, 34426522, 33989670, 33207704, 32707200, 36586411, 36927399, Blank2021[paper], 35729334, 33401496, 31874111, 35753512, 34596024, 34014414, O'Sullivan2021[paper], 35621220, 19302049, 15593220)
Illumina Laboratory Services, 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	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000223458	SCV001147801	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	NLRP3: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223458	SCV001157330	uncertain significance	not provided	2023-08-10	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% (188/281,098 alleles) in the Genome Aggregation Database. The arginine at codon 490 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.591). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of the p.Arg490Lys variant is uncertain at this time. 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. PMID: 15593220. Haverkamp MH et al. Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS). Clin Exp Immunol. 2014 Sep;177(3):720-31. PMID: 24773462. 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. PMID: 28692792. 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. PMID: 29077208. 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. PMID: 23421920.
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
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262693	SCV002542602	uncertain significance	Autoinflammatory syndrome	2021-03-22	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