ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.1312A>G (p.Thr438Ala) (rs180177465)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000433450 SCV000512626 likely pathogenic not provided 2016-12-19 criteria provided, single submitter clinical testing The T438A variant has been published previously in association with an NLRP3-associated disorder (Zeft et al., 2007). 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. T438A is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the NACHT domain where amino acids with similar properties to Threonine are tolerated across species. The NACHT domain is a known locus for pathogenic variants (Masters et al., 2009), and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, T438A has been reported to impair expression of the NLRP3 protein; however, the authors did not publish their data (Guo et al., 2016). Missense variants in the same residue (T438P/I/N) and in nearby residues (T435I, K437E, A441P/T/V, Y443H) have been reported in the Human Gene Mutation Database in association with NLRP3-associated disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic.
Invitae RCV000707213 SCV000836301 uncertain significance Cryopyrin associated periodic syndrome 2018-06-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 438 of the NLRP3 protein (p.Thr438Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with cryopyrin-associated periodic syndrome (CAPS) (PMID: 17513575, 27191192 ). This variant is also known as c.1306A>G p.T436A in the literature. ClinVar contains an entry for this variant (Variation ID: 97921). In an experimental study, this missense change resulted in decreased expression of the NLRP3 protein product (PMID: 27692610). The clinical significance of these results is uncertain. Other variants that disrupt the p.Thr438 amino acid residue in NLRP3 have been observed in affected individuals (PMID: 26245507, 14630794, 28501347, 12032915). This suggests that it is a clinically significant residue, and that variants that disrupt this residue may be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084180 SCV000116312 not provided Familial cold urticaria no assertion provided not provided

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