ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.1049C>T (p.Thr350Met) (rs151344629)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214584 SCV000278941 pathogenic not provided 2017-11-14 criteria provided, single submitter clinical testing The T350M missense change in the NLRP3 gene has been previously reported as T348M in association with Muckle-Wells syndrome (Dode et al., 2002; Rieber et al., 2015; Salugina et al., 2014) and CINCA syndrome (Neven et al., 2004; Lepore et al., 2010; Kanariou et al., 2014). It is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). T350M is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although this substitution occurs at a position where amino acids with similar properties to Threonine are tolerated across species, in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (V353M/L, A354V/T, L355P) have been reported in the Human Gene Mutation Database in association with NLRP3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret T350M as pathogenic.
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.
Invitae RCV000540218 SCV000646260 pathogenic Cryopyrin associated periodic syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 350 of the NLRP3 protein (p.Thr350Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (rs151344629, ExAC no frequency). This variant has been reported as a common variant identified in individuals affected with NLRP3-related diseases with strong evidence of disease co-segregation (PMID: 21356079, 20472245, 26931528, 16100350, 26245507, 26531310, 23442610, 17178739, 25730877, 17178739, 25730877, 11992256). This variant is also known as p.Thr348Met in the literature (PMID: 16100350). ClinVar contains an entry for this variant (Variation ID: 97909). Blood leukocytes or monocytes from affected individuals with this variant showed abnormal inflammatory responses triggered by microbial antigens (PMID: 16100350, 25730877). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000214584 SCV001371568 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084167 SCV000116298 not provided Familial cold urticaria no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.