ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.2767A>G (p.Thr923Ala) (rs200089542)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000220153 SCV000279254 uncertain significance not provided 2015-04-01 criteria provided, single submitter clinical testing The T923A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It 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. T923A 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. However, this substitution occurs at a position that is not conserved across species, with an Alanine residue being tolerated at this position. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000337870 SCV000357001 uncertain significance Familial amyloid nephropathy with urticaria AND deafness 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000394837 SCV000357002 uncertain significance Chronic infantile neurological, cutaneous and articular syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000298441 SCV000357003 uncertain significance Familial cold autoinflammatory syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000813164 SCV000953509 uncertain significance Cryopyrin associated periodic syndrome 2018-07-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 923 of the NLRP3 protein (p.Thr923Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs200089542, ExAC 0.009%). This variant has not been reported in the literature in individuals with NLRP3-related disease. ClinVar contains an entry for this variant (Variation ID: 234451). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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