Submissions for variant NM_001243133.2(NLRP3):c.404G>A (p.Arg135His)

gnomAD frequency: 0.00029  dbSNP: rs138946894

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000219739	SCV000278934	uncertain significance	not provided	2019-09-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also denoted as R135H due to alternative nomenclature; This variant is associated with the following publications: (PMID: 26774591, 26299986, 21058222)
CeGaT Center for Human Genetics Tuebingen	RCV000219739	SCV001147799	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	NLRP3: BP4, BS2
Invitae	RCV001067333	SCV001232388	uncertain significance	Cryopyrin associated periodic syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 137 of the NLRP3 protein (p.Arg137His). This variant is present in population databases (rs138946894, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Muckle-Wells syndrome (PMID: 21058222). This variant is also known as R135H. ClinVar contains an entry for this variant (Variation ID: 234288). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NLRP3 protein function. 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, Mass General Brigham 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262813	SCV002542635	uncertain significance	Autoinflammatory syndrome	2021-02-26	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288904	SCV002581636	uncertain significance	Familial amyloid nephropathy with urticaria AND deafness	2022-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002516185	SCV003760756	uncertain significance	Inborn genetic diseases	2022-05-10	criteria provided, single submitter	clinical testing	The c.410G>A (p.R137H) alteration is located in exon 3 (coding exon 3) of the NLRP3 gene. This alteration results from a G to A substitution at nucleotide position 410, causing the arginine (R) at amino acid position 137 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.