ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.2993G>C (p.Cys998Ser) (rs199517145)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000756446 SCV000278952 uncertain significance not provided 2013-08-22 criteria provided, single submitter clinical testing To our knowledge, the C998S missense substitution has neither been published as a mutation, nor reported as a benign polymorphism. The NHLBI ESP Exome Variant Server reports that C998S was not observed at a significant frequency in individuals of African American or European backgrounds, indicating it is not a common benign variant in these populations. Although Cysteine and Serine are both neutral, polar amino acids, C998S represents a non-conservative amino acid substitution as the loss of a Cysteine residue can impact normal disulfide bonds within the NLRP3 protein. The position in the NLRP3 protein where this substitution occurs is highly conserved among species; however, it is not located in the NACHT/NBD domain, which is the domain where nearly all NLRP3 disease-associated mutations have been identified. Therefore, based on the currently available information, it is unclear whether C998S is a disease-causing mutation or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756446 SCV000884264 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing The NLRP3 c.2993G>C ; p.Cys998Ser variant (rs199517145) to our knowledge, is not reported in the medical literature or in gene specific variant databases. The variant is listed in the ClinVar database (Variation ID: 234294). This variant is found in the general population in 11/276958 alleles in the Genome Aggregation Database. The cysteine at this position is well conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, the clinical significance of this variant cannot be determined with certainty. Pathogenic NLRP3 variants are causative for autosomal dominant CINCA syndrome, autosomal dominant deafness with or without inflammation, familial cold-induced inflammatory syndrome, or Muckle-Wells syndrome (MIM: 606416).
Invitae RCV001241011 SCV001414000 uncertain significance Cryopyrin associated periodic syndrome 2019-05-15 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 998 of the NLRP3 protein (p.Cys998Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs199517145, ExAC 0.006%). This variant has not been reported in the literature in individuals with NLRP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 234294). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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