Submissions for variant NM_001243133.2(NLRP3):c.778C>T (p.Arg260Ter)

dbSNP: rs121908150

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221297	SCV000278937	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as p.(R260W); This variant is associated with the following publications: (PMID: 26931528, 29331074, 29196621, 28569730, 20472245, 25596455, 17178985, 24501247, 11992256, 29773275, 28716882, 19302049, 23703389, 15020601, 31086329)
Invitae	RCV001067187	SCV001232233	pathogenic	Cryopyrin associated periodic syndrome	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 262 of the NLRP3 protein (p.Arg262Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cryopyrin-associated periodic syndromes (CAPS) (PMID: 11992256, 20472245). It has also been observed to segregate with disease in related individuals. This variant is also known as R260W. The NLRP3 gene is also known as CIAS1 in the literature. ClinVar contains an entry for this variant (Variation ID: 4374). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 15020601, 23703389). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000221297	SCV001472486	pathogenic	not provided	2019-12-23	criteria provided, single submitter	clinical testing	The NLRP3 c.784C>T; p.Arg262Trp variant (rs121908150), also known as R260W in traditional nomenclature, is reported in the literature in multiple individuals and segregates with disease in families affected with cryopyrin-associated periodic syndrome (CAPS) (Alejandre 2014, Dode 2002, Lepore 2010, Parker 2016, Rieber 2015). This variant is reported in ClinVar (Variation ID: 4374), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 262 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate defects in inflammasome activation (Rieber 2015). Additionally, other variants at this codon (c.785G>T, p.Arg262Leu; c.785G>C, p.Arg262Pro) have been reported in individuals with CAPS (Neven 2004). Based on available information, this variant is considered to be pathogenic. References: Alejandre N et al. Description of a new family with cryopyrin-associated periodic syndrome: risk of visual loss in patients bearing the R260W mutation. Rheumatology (Oxford). 2014 Jun;53(6):1095-9. Dode C et al. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet. 2002 Jun;70(6):1498-506. Lepore L et al. Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with Anakinra. J Pediatr. 2010 Aug;157(2):310-315.e1. Neven B et al. Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood. 2004 Apr 1;103(7):2809-15. Parker T et al. Neurology of the cryopyrin-associated periodic fever syndrome. Eur J Neurol. 2016 Jul;23(7):1145-51. Rieber N et al. A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants. Clin Immunol. 2015 Mar;157(1):56-64.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262556	SCV002542644	pathogenic	Autoinflammatory syndrome	2021-03-26	criteria provided, single submitter	clinical testing
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 autoinflammatory syndrome 1	2002-06-01	no assertion criteria provided	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000004623	SCV000116365	not provided	Familial cold autoinflammatory syndrome 1		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000221297	SCV001927539	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000221297	SCV001958597	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000221297	SCV001963356	pathogenic	not provided		no assertion criteria provided	clinical testing