ClinVar Miner

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

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Total submissions: 5
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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 2018-07-30 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.
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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