ClinVar Miner

Submissions for variant NM_001243133.2(NLRP3):c.2018G>A (p.Arg673Gln)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001214474 SCV001386157 uncertain significance Cryopyrin associated periodic syndrome 2019-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 675 of the NLRP3 protein (p.Arg675Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs142651552, ExAC 0.06%). This variant has been observed in several individuals affected with periodic fever, however some of these individuals also carried variants in other genes also associated with periodic fever (PMID: 25866490). This variant is referred to as rs142651552/c.2024G>A Q705K in the literature, however, it is likely that the reported protein effect of Q705K is an error. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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