ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.1322C>T (p.Ala441Val) (rs121908146)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214900 SCV000278944 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing The A441V missense variant in the NLRP3 gene has been reported previously as A439V in association with Familial Cold Autoinflammatory syndrome (Hoffman et al., 2001; Aoyama et al., 2012). The variant is not observed in large population cohorts (Lek et al., 2016). This pathogenic variant occurs in the NACHT/NBD domain of the NLRP3 protein, which is where the majority of pathogenic variants have been identified. Functional studies confirm that individuals with A441V have increased secretion of inflammatory cytokines, which correlates with disease severity (Rieber et al., 2015). Therefore, the presence of A441V is consistent with the diagnosis of a cryopyrin-associated disorder
Invitae RCV000701554 SCV000830359 pathogenic Cryopyrin associated periodic syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 441 of the NLRP3 protein (p.Ala441Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with NLRP3-related disease (PMID: 26931528, 25596455, 26245507, 27134254, 15801036, 11687797). This variant is also known as A439V or C1316T in the literature. ClinVar contains an entry for this variant (Variation ID: 4370). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999878 SCV000885859 pathogenic not specified 2018-08-01 criteria provided, single submitter clinical testing The NLRP3 c.1322C>T; p.Ala441Val variant (rs121908146), also known as Ala439Val, is published in the medical literature in several individuals and families with various autoinflammatory syndromes (Aoyama 2012, Hentgen 2005, Hoffman 2001, Houx 2015, Parker 2016) and is described as one of the more common pathogenic variants (Cuisset 2010). The variant is described as occurring de novo in at least one family (Hoffman 2001) and also has been shown to segregate with disease (Hoffman 2001, Hentgen 2005). The variant is listed in the ClinVar database (Variation ID: 4370), but is not listed in the general population-based databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at this position is well conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. Pathogenic NLRP3 variants are associated with autosomal dominant cryopyrin-associated periodic fevers (MIM#606416). References: Aoyama K et al. Cryopyrin-associated periodic syndrome: a case report and review of the Japanese literature. Acta Derm Venereol. 2012 Jul;92(4):395-8. Cuisset L et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011 Mar;70(3):495-9. Hentgen V et al. Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome. J Rheumatol. 2005 Apr;32(4):747-51. Hoffman HM et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301-5. Houx L et al. Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study. Arthritis Rheumatol. 2015 Nov;67(11):3027-36. Parker T et al. Neurology of the cryopyrin-associated periodic fever syndrome. Eur J Neurol. 2016 Jul;23(7):1145-51.
OMIM RCV000004618 SCV000024792 pathogenic Familial cold urticaria 2001-11-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000004618 SCV000116318 not provided Familial cold urticaria no assertion provided not provided

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