ClinVar Genomic variation as it relates to human health

The NLRP3 c.913G>A;p.Asp305Asn (also known as Asp303Asn) variant is published in the medical literature in individuals with Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease (NOMID) (Dode 2002, Eungdamrong 2013, Feldmann 2002,Haverkamp 2014). Additionally, a mouse model with this variant recapitulates the disease (Qu 2015). The variant is listed in the ClinVar database (Variation ID: 4377), and in the dbSNP variant database (rs121908153), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The aspartic acid at codon 305 is well conserved across mammals and computational programs (PolyPhen2, SIFT) predict this variant to be deleterious. Taken together, this variant is considered pathogenic. Pathogenic NLRP3 variants are associated with CINCA syndrome (MIM#607115), familial cold-induced inflammatory syndrome (MIM#120100), and Muckle-Wells syndrome (MIM#191900). 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. Eungdamrong J et al. Muckle-Wells treatment with anakinra. Dermatol Online J. 2013 19(12):20720. Feldmann J et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet.2002 71(1):198-203. Haverkamp MH et al. Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS). Clin Exp Immunol. 2014 177(3):720-31. Qu C et al. NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms. FASEB J. 2015 29(4):1269-79.

This variant is denoted c.913 G>A at the cDNA level or p.Asp305Asn (D305N) at the protein level. Please note that this mutation is also referred to as D303N due to a difference in the convention of naming the first codon of the NLRP3 gene. The D305N missense mutation in the NLRP3 gene has been previously reported in association with Muckle-Wells syndrome (Dode et al, 2002) and CINCA syndrome (Neven et al., 2004). Therefore, its presence is consistent with a diagnosis of a cryopyrin-associated disease.

PM1, PS3, PP3, PS4, PM2_SUP

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 305 of the NLRP3 protein (p.Asp305Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NLRP3-associated conditions, including Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease, with evidence of disease co-segregation (PMID: 11992256, 24365011, 24773462, 25766347, 26590045). 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 also known as G907A D303N. ClinVar contains an entry for this variant (Variation ID: 4377). 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: 15020601, 22193915, 24517500). This variant disrupts the p.Asp305 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 14630794, 21702021), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.