ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.913G>A (p.Asp305Asn) (rs121908153)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214348 SCV000278938 pathogenic not provided 2014-01-30 criteria provided, single submitter clinical testing 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.
Invitae RCV000527671 SCV000646276 pathogenic Cryopyrin associated periodic syndrome 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 305 of the NLRP3 protein (p.Asp305Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals and families affected with NLRP3-associated conditions, including Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease, with evidence of disease co-segregation (PMID: 11992256, 24365011, 25766347, 24773462, 26590045). This variant is also known as p.Asp303Asn in the literature. CilnVar contains an entry for this variant (Variation ID: 4377). Experimental studies have shown that this missense change caused elevated inflammatory responses in vitro (PMID: 22193915, 24517500, 15020601). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000214348 SCV000885860 pathogenic not provided 2017-10-25 criteria provided, single submitter clinical testing 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.
OMIM RCV000004626 SCV000024800 pathogenic Chronic infantile neurological, cutaneous and articular syndrome 2002-07-01 no assertion criteria provided literature only
OMIM RCV000004627 SCV000024801 pathogenic Familial amyloid nephropathy with urticaria AND deafness 2002-07-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084240 SCV000116376 not provided Familial cold urticaria no assertion provided not provided

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