ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.410G>A (p.Arg137His) (rs138946894)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219739 SCV000278934 uncertain significance not provided 2016-07-19 criteria provided, single submitter clinical testing The R137H variant in the NLRP3 gene has been previously reported in two individuals with clinical findings consistent with a cryopyrin-associated periodic syndrome (Hernandez-Rodriguez et al., 2015; Lainka et al., 2010). However, this variant was also reported in another individual with lymphoma who was found to have an alternate molecular explanation for her features (Sharapova et al., 2016). Adidtionally, the NHLBI ESP Exome Sequencing Project reports R137H was observed in 5/8600 (0.06%) alleles from individuals of European American background, indicating it may be a rare benign variant in this population. The R137H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret R137H as a variant of uncertain significance, which may be related to hepatosplenomegaly and lymphocyte infiltration.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000219739 SCV001147799 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
Invitae RCV001067333 SCV001232388 uncertain significance Cryopyrin associated periodic syndrome 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 137 of the NLRP3 protein (p.Arg137His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs138946894, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with Muckle-Wells syndrome (PMID: 21058222). ClinVar contains an entry for this variant (Variation ID: 234288). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195580 SCV001365975 likely benign not specified 2020-03-04 criteria provided, single submitter clinical testing The p.Arg137His variant in NLRP3 is classified as likely benign because it has been identified in 0.05% (63/128894) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1.

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