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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000214900 SCV000885859 pathogenic not provided 2018-01-24 criteria provided, single submitter clinical testing
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 2019-01-06 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.
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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