ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.1942G>T (p.Asp648Tyr) (rs138061418)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523103 SCV000616680 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing The D648Y variant has been published previously in association with chronic spontaneous urticaria (Herbert et al., 2015). The variant is observed in 3/66722 (0.004%) alleles from individuals of European background in the ExAC dataset (Lek et al., 2016). D648Y 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, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001040235 SCV001203797 uncertain significance Cryopyrin associated periodic syndrome 2019-03-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 648 of the NLRP3 protein (p.Asp648Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs138061418, ExAC 0.004%). This variant has been observed in a family with clinical features suspicious for cryopyrin associated periodic fever syndrome (CAPS) (PMID: 25732894). ClinVar contains an entry for this variant (Variation ID: 449000). 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: "Benign"; Align-GVGD: "Class C15"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000523103 SCV001371569 uncertain significance not provided 2020-04-01 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000523103 SCV000920731 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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