ClinVar Miner

Submissions for variant NM_004895.5(NLRP3):c.1223T>C (p.Met408Thr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001053828 SCV001218110 uncertain significance Cryopyrin associated periodic syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 408 of the NLRP3 protein (p.Met408Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features consistent with cryopyrin-associated periodic syndrome (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Met408 amino acid residue, also known as p.Met406 in the literature, in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 16920754, 21702021), which suggests that this may be a clinically significant amino acid residue. 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.

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