Submissions for variant NM_001243133.2(NLRP3):c.592G>A (p.Val198Met)

gnomAD frequency: 0.00835  dbSNP: rs121908147

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224634	SCV000280952	likely benign	not provided	2016-05-12	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
PreventionGenetics, part of Exact Sciences	RCV004528070	SCV000310710	likely benign	NLRP3-related disorder	2019-09-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Illumina Laboratory Services, Illumina	RCV000312024	SCV000356923	likely benign	Familial cold autoinflammatory syndrome	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000224634	SCV000490471	uncertain significance	not provided	2020-01-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the V200M variant results in moderate increase of interleukin-1 beta secretion, and NLRP3/cryopyrin inflammosome activation (Yuksel et al., 2014); Is considered by some as a risk allele or variant with reduced penetrance (Aksentijevich et al., 2007; Yuksel et al., 2014; Kuemmerle-Deschner et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24123366, 26531310, 30407166, 17393462, 24135410, 25988833, 23421920, 12355493, 20159265, 26020059, 25596455, 15334488, 11687797, 17038455, 22566169, 27994174, 29159471, 29922587, 28692792, 31858722, 30783801, 31036385, 31769854, 31410474, 14872505)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224634	SCV000604557	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	The NLRP3 c.598G>A; p.Val200Met variant (rs121908147), also known as V198M, is listed in the Genome Aggregation Database with an allele frequency of up to 2.3% (588/25096 alleles, including 6 homozygotes) in the European Finnish population. The valine at codon 200 is weakly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.222). The variant is listed in the ClinVar database with conflicting classifications (Variation ID: 4371). This variant is reported in the medical literature in individuals with familial cold-induced autoinflammatory syndrome (FCAS) (MIM:120100) and Muckle-Wells syndrome (MWS) (MIM:191900), both also known as cryopyrin-associated periodic syndromes (CAPS), as well as in patients with other autoinflammatory syndromes, acquired disorders including Schnitzler syndrome, and also in asymptomatic carriers (Aganna 2002, Hoffman 2001, Kuemmerle-Deschner 2017, Rowczenio 2013, Torres 2018, Yuksel 2014). Since p.Val200Met presents with variable expressivity and reduced penetrance, this variant may contribute to the inflammatory diseases processes together with other, presently unidentified, genetic and environmental factors. However, the existence of individuals homozygous for the variant in control databases and the high population frequency suggest this variant is benign. Due to conflicting information, the clinical significance of the p.Val200Met variant is uncertain at this time. References: Aganna E et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 2002 46(9):2445-2452. PMID: 12355493 Hoffman HM et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflamatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 29(3):301-305. PMID: 11687797 Kuemmerle-Deschner JB et al. Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges. Arthritis Rheumatol. 2017 Nov;69(11):2233-2240. PMID: 28692792. Rowczenio DM et al. Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature. Arthritis Res Ther. 2013 15(1):R30. PMID: 23421920 Torres A et al. De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome. Mol Genet Metab Rep. 2018 Jun 15;16:23-29. PMID: 29922587. Yuksel S. et al. Novel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behcet’s syndrome patients. Int Immunol. 2014 26(2):71-81. PMID: 24135410.
Invitae	RCV001082121	SCV000646274	benign	Cryopyrin associated periodic syndrome	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224634	SCV000891898	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	NLRP3: BP4, BS2
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000509555	SCV000898853	uncertain significance	Chronic infantile neurological, cutaneous and articular syndrome; Familial amyloid nephropathy with urticaria AND deafness; Familial cold autoinflammatory syndrome 1	2020-02-13	criteria provided, single submitter	clinical testing	NLRP3 NM_004895.4 exon 3 p.Val200Met (c.598G>A): This variant has been reported in the literature in the heterozygous and double heterozygous state in several individuals with clinical features consistent with NLRP3 related abnormal inflammatory response (e.g. Familial Cold Autoinflammatory Syndrome, Muckle-Wells syndrome) (Hoffman 2001 PMID:11687797, Aganna 2002 PMID:12355493, Loock 2010 PMID:20159265, Yuksel 2014 PMID:24135410, Kemmerle-Deschner 2015 PMID:26531310, Neocleous 2016 PMID: 27994174). In some reports, the variant also segregated in other family members with variable clinical features of disease. However, this variant is present in 2.4% (588/25096) of Finnish alleles, including 6 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-247587343-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar with several discrepant classifications from "Benign to Variant of Uncertain Significance" (Variation ID:4371). This variant amino acid Methionine (Met) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Functional studies suggest that this variant will impact the protein NLRP3/cryopyrin inflammosome (Yuksel 2014 PMID:24135410); however, further studies are needed to understand its impact. Of note, at least 2 authors in the literature suggest that this variant may act as a risk allele or low penetrance variant (Aganna 2002 PMID:12355493, Yuksel 2014 PMID:24135410). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000004619	SCV000930272	likely benign	Familial cold autoinflammatory syndrome 1	2019-04-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791008	SCV000930273	likely benign	Hearing loss, autosomal dominant 34, with or without inflammation	2019-04-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000248492	SCV000966485	likely benign	not specified	2018-02-10	criteria provided, single submitter	clinical testing	p.Val200Met in exon 5 of NLRP3: This variant (also reported as p.Val198Met) is n ot expected to have clinical significance because it has been identified in 0.85 % (2343/276948) of the total chromosomes in the Genome Aggregation Database incl uding 19 homozygotes. The highest allele frequency was 2.38% (613/25766) of Fin nish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs121908147). The NLRP3 gene is associated with cryopyrin associated periodic syndrome (CAPS) which has an estimated prevalence of 1 in 36 0,000 (Orphanet, http://www.orpha.net, Orpha # 208650). While this variant has been reported in many individuals with features of CAPS and has been reported as a "low-penetrance allele", the variant was also identified in controls and unaf fected family members (Aggana 2002, Rowczenio 2013, Hoffman 2001, Look 2010, Lev y 2015). Furthermore, the frequency of the variant in the affected individuals in several studies was similar to the frequency of the variant in the Genome Agg regation Database (Kone-Paut 2007, Jesus 2012, Rowczenio 2013, Schuh 2015). One study found that in transfected embryonal kidney cells with the p.Val200Met var iant, IL-1? secretion was significantly increased compared to wild-type transfe cted cells (Yuksel 2014). However, another study found that patients with Val19 8Met and other variants described as low-penetrance alleles had similar response s as controls to inflammasome stimulation, compared with patients with clearly p athogenic NLRP3 variants (Rieber 2015). Furthermore, the valine (Val) residue a t position 200 is not conserved through species with >10 mammals having a methio nine (Met) at this position. In summary, due to the high frequency of the varia nt in the general population compared to the low estimated prevalence of CAPS, a nd the absence of enrichment of the variant in affected individuals, this varian t is likely benign. ACMG/AMP criteria applied: BS1, BS4, BP4.
Mendelics	RCV000004619	SCV001135610	benign	Familial cold autoinflammatory syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000224634	SCV001475324	uncertain significance	not provided	2020-07-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224634	SCV001715676	uncertain significance	not provided	2022-10-12	criteria provided, single submitter	clinical testing	BS1, BS2, BP4, PS4
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262554	SCV002542638	uncertain significance	Autoinflammatory syndrome	2022-04-25	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002293975	SCV002587730	uncertain significance	Kidney disorder	2021-12-02	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224088	SCV003920290	uncertain significance	Chronic infantile neurological, cutaneous and articular syndrome; Keratitis fugax hereditaria; Familial amyloid nephropathy with urticaria AND deafness; Familial cold autoinflammatory syndrome 1; Hearing loss, autosomal dominant 34, with or without inflammation	2022-10-13	criteria provided, single submitter	clinical testing	NLRP3 NM_004895.4 exon3 p.Val200Met (c.598G>A): This variant has been reported in the literature in the heterozygous and double heterozygous state in several individuals with clinical features consistent with NLRP3 related abnormal inflammatory response (e.g. Familial Cold Autoinflammatory Syndrome, Muckle-Wells syndrome) (Hoffman 2001 PMID:11687797, Aganna 2002 PMID:12355493, Loock 2010 PMID:20159265, Yuksel 2014 PMID:24135410, Kemmerle-Deschner 2015 PMID:26531310, Neocleous 2016 PMID: 27994174). In some reports, the variant also segregated in other family members with variable clinical features of disease. However, this variant is present in 2.4% (613/25766) of Finnish alleles, including 6 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121908147). This variant is present in ClinVar with several discrepant classifications from "Benign to Variant of Uncertain Significance" (Variation ID:4371). This variant amino acid Methionine (Met) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Functional studies suggest that this variant will impact the protein NLRP3/cryopyrin inflammosome (Yuksel 2014 PMID:24135410); however, further studies are needed to understand its impact. Of note, at least 2 authors in the literature suggest that this variant may act as a risk allele or low penetrance variant (Aganna 2002 PMID:12355493, Yuksel 2014 PMID:24135410). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
OMIM	RCV000004619	SCV000024793	pathogenic	Familial cold autoinflammatory syndrome 1	2001-11-01	no assertion criteria provided	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000004619	SCV000116361	not provided	Familial cold autoinflammatory syndrome 1		no assertion provided	not provided
GenomeConnect, ClinGen	RCV000509555	SCV000607138	not provided	Chronic infantile neurological, cutaneous and articular syndrome; Familial amyloid nephropathy with urticaria AND deafness; Familial cold autoinflammatory syndrome 1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.