ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.1064T>C (p.Leu355Pro) (rs28937896)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219571 SCV000278942 pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing The L355P missense variant in the NLRP3 gene has been previously reported in association with NLRP3-related disorders (Hoffman et al. 2003; Tran et al., 2012); therefore, this result is consistent with a diagnosis of a cryopyrin-associated disease . The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. L355P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the NACHT domain that is conserved in mammals, and where gain-of-function variants are known to cause NLRP3-related disorders (Lamkanfi et al., 2010). Missense variants in nearby residues (T350M, V353L/M, A354V, E356D, K357T/N, H360R) 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.
Fulgent Genetics,Fulgent Genetics RCV000762894 SCV000893294 pathogenic Chronic infantile neurological, cutaneous and articular syndrome; Keratitis fugax hereditaria; Familial amyloid nephropathy with urticaria AND deafness; Familial cold urticaria; DEAFNESS, AUTOSOMAL DOMINANT 34, WITH OR WITHOUT INFLAMMATION 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000795773 SCV000935247 pathogenic Cryopyrin associated periodic syndrome 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 355 of the NLRP3 protein (p.Leu355Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with familial cold autoinflammatory syndrome (FCAS) in several families (PMID: 12522564, 16081838). In addition, it has been reported in multiple individuals affected with FCAS and Muckle-Wells syndrome (PMID: 22512814, 21109514, 17393462, 24773462), and has been described as a well known disease causing variant (PMID: 22661645). This variant is also known as T1058C and Leu353Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 4379). Experimental studies have shown that this missense change has a gain-of-function effect leading to inflammasome activation (PMID: 28692792, 19501000). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000586 SCV001157565 pathogenic not specified 2019-02-05 criteria provided, single submitter clinical testing The NLRP3 c.1064T>C; p.Leu355Pro variant (rs28937896), also known as p.Leu353Pro using traditional nomenclature, is reported in the literature in multiple individuals and families affected with familial cold autoinflammatory syndrome or Muckle-Wells syndrome (Hoffman 2003, Tran 2012). In three families, this variant occurred within a haplotype that co-segregated with disease in multiple affected individuals and was absent from unaffected relative (Hoffman 2003). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 355 is highly conserved, computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and it occurs in the functionally important NACHT nucleotide hydrolase domain adjacent to other disease-associated missense variants reported in the Human Gene Mutation Database (Stenson 2014). Additionally, a genetic mouse model carrying a heterozygous variant orthologous to p.Leu355Pro exhibits neonatal lethality attributed to hyperactive immune signaling (Brydges 2009). Based on available information, the p.Leu355Pro variant is considered to be pathogenic. References: Brydges SD et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity. 2009 Jun 19;30(6):875-87. Hoffman HM et al. Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P. Hum Genet. 2003 Feb;112(2):209-16. Stenson PD et al. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014 Jan;133(1):1-9. Tran TA et al. Muckle-Wells syndrome and male hypofertility: a case series. Semin Arthritis Rheum. 2012 Dec;42(3):327-31.
OMIM RCV000004629 SCV000024803 pathogenic Familial cold urticaria 2003-02-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000004629 SCV000116303 not provided Familial cold urticaria no assertion provided not provided

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