ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.2674G>T (p.Val892Leu) (rs193085132)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756445 SCV000884263 uncertain significance not provided 2017-10-13 criteria provided, single submitter clinical testing The NLRP3 c.2674G>T; p.Val892Leu variant is not published in the medical literature, in gene-specific databases, or in the ClinVar database. The variant is listed in the dbSNP variant database (rs193085132), in the Exome Variant Server with an allele frequency of 0.0231 percent (3/13003 alleles), and in the Genome Aggregation Database with an allele frequency of 0.006498 percent (18/277012 alleles). The valine at this position is moderately conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. Pathogenic NLRP3 variants are causative for autosomal dominant CINCA syndrome (MIM#607115), familial cold-induced inflammatory syndrome (MIM#120100), and Muckle-Wells syndrome (MIM#191900).
Invitae RCV000798087 SCV000937684 uncertain significance Cryopyrin associated periodic syndrome 2018-07-19 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 892 of the NLRP3 protein (p.Val892Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs193085132, ExAC 0.07%). This variant has not been reported in the literature in individuals with NLRP3-related disease. 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. 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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