Submissions for variant NM_001243133.2(NLRP3):c.1043C>T (p.Thr348Met)

dbSNP: rs151344629

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214584	SCV000278941	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27435956, 14630794, 21356079, 26531310, 27353043, 23442610, 17178739, 25730877, 34979568, 31816408, 33042144, 20472245, 25349319, 24952504, 26931528, 11992256, 28028683, 28501347, 25596455, 16100350, 26245507, 30184330, 30273710, 23486414, 15593220, 32152129, 34099780)
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000449533	SCV000537730	pathogenic	Familial amyloid nephropathy with urticaria AND deafness	2014-08-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000214584	SCV000604551	pathogenic	not provided	2018-01-24	criteria provided, single submitter	clinical testing	The NLRP3 c.1049C>T;p.Thr350Met (rs151344629), also known as Thr348Met, is published in the literature in individuals with various periodic fever syndromes (Kuemmerle-Deschner 2011, Kuemmerle-Deschner 2015). The variant has been described both as occurring de novo and as segregating with disease (Dode 2002, Kanariou 2014). The variant is listed as pathogenic in the ClinVar database (Variation ID: 97909). The variant is not listed in the general population databases (Exome Variant Server, Exome Aggregation Consortium), indicating it is not a common polymorphism. The threonine at codon 350 is moderately conserved across a variety of species and computational programs (Align GVGD, SIFT) predict this variant is deleterious to protein function. Considering available information, this variant is classified as pathogenic. Pathogenic NLRP3 variants are causative for autosomal dominant Muckle-Wells syndrome (MIM#606416). References: 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 70(6):1498-506. Kanariou M et al. Successful management of cryopyrin-associated periodic syndrome with canakinumab in infancy. Pediatrics. 2014 134(5):e1468-73. Kuemmerle-Deschner JB et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1B mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther. 2011 13(1):R34. Kuemmerle-Deschner JB et al. Early detection of sensorineural hearing loss in Muckle-Wells-syndrome. Pediatr Rheumatol Online J. 2015 13(1):43.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540218	SCV000646260	pathogenic	Cryopyrin associated periodic syndrome	2022-11-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 16100350, 25730877). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 97909). This variant is also known as p.Thr348Met. This missense change has been observed in individual(s) with clinical features of NLRP3-related conditions (PMID: 11992256, 16100350, 17178739, 20472245, 21356079, 23442610, 25730877, 26245507, 26531310, 26931528). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 350 of the NLRP3 protein (p.Thr350Met).
CeGaT Center for Human Genetics Tuebingen	RCV000214584	SCV001371568	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	NLRP3: PP1:Strong, PM1, PM2, PS4:Moderate, PP4
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262687	SCV002542584	pathogenic	Autoinflammatory syndrome	2021-04-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002464107	SCV002759335	pathogenic	Chronic infantile neurological, cutaneous and articular syndrome; Familial amyloid nephropathy with urticaria AND deafness	2022-12-07	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000084167	SCV000116298	not provided	Familial cold autoinflammatory syndrome 1		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000214584	SCV001927271	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000214584	SCV001957276	pathogenic	not provided		no assertion criteria provided	clinical testing