ClinVar Genomic variation as it relates to human health

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.

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.

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 355 of the NLRP3 protein (p.Leu355Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial cold autoinflammatory syndrome (FCAS) and FCAS and Muckle-Wells syndrome (PMID: 12522564, 16081838, 17393462, 21109514, 22512814, 22661645, 24773462). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NLRP3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 19501000, 28692792). For these reasons, this variant has been classified as Pathogenic.

PP1_moderate, PP3, PP4, PM2, PS3_supporting, PS4