VCV000004371.68 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(20)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(8); Benign(2); Likely benign(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 4371 Accession: VCV000004371.68

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q44 1: 247424041 (GRCh38) [ NCBI UCSC ] 1: 247587343 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 6, 2014	Oct 20, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001243133.2:c.592G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230062.1:p.Val198Met	missense
NM_001079821.3:c.592G>A	NP_001073289.2:p.Val198Met	missense
NM_001127461.3:c.592G>A	NP_001120933.2:p.Val198Met	missense
NM_001127462.3:c.592G>A	NP_001120934.2:p.Val198Met	missense
NM_004895.5:c.598G>A	NP_004886.3:p.Val200Met	missense
NM_183395.3:c.592G>A	NP_899632.2:p.Val198Met	missense
NC_000001.11:g.247424041G>A
NC_000001.10:g.247587343G>A
NG_007509.2:g.12869G>A
LRG_197:g.12869G>A
LRG_197t1:c.598G>A	LRG_197p1:p.Val200Met

... more HGVS ... less HGVS

Protein change

V198M, V200M

Other names

Canonical SPDI

NC_000001.11:247424040:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00399 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00390

1000 Genomes Project 0.00399

Trans-Omics for Precision Medicine (TOPMed) 0.00581

The Genome Aggregation Database (gnomAD) 0.00835

Links

ClinGen: CA280962 OMIM: 606416.0002 dbSNP: rs121908147 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NLRP3		-	-	GRCh38 GRCh38 GRCh37	982	1065

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Familial cold autoinflammatory syndrome 1	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Aug 22, 2023	RCV000004619.21
not provided	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Jun 1, 2024	RCV000224634.51
not specified	Likely benign (1)	criteria provided, multiple submitters, no conflicts	Feb 10, 2018	RCV000248492.21
Familial cold autoinflammatory syndrome	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000312024.13
Hearing loss, autosomal dominant 34, with or without inflammation	Likely benign (1)	criteria provided, single submitter	Apr 27, 2019	RCV000791008.11
Chronic infantile neurological, cutaneous and articular syndrome Familial amyloid nephropathy with urticaria AND deafness Familial cold autoinflammatory syndrome 1	Uncertain significance (2)	criteria provided, single submitter	Feb 13, 2020	RCV000509555.12
Autoinflammatory syndrome	Uncertain significance (1)	criteria provided, single submitter	Apr 25, 2022	RCV002262554.10
Cryopyrin associated periodic syndrome	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001082121.14
NLRP3-related disorder	Likely benign (1)	no assertion criteria provided	Sep 16, 2019	RCV004528070.2
Kidney disorder	Uncertain significance (1)	criteria provided, single submitter	Dec 2, 2021	RCV002293975.9
Chronic infantile neurological, cutaneous and articular syndrome Familial amyloid nephropathy with urticaria AND deafness Familial cold autoinflammatory syndrome 1 Hearing loss, autosomal dominant 34, with or without inflammation Keratitis fugax hereditaria	Uncertain significance (1)	criteria provided, single submitter	Oct 13, 2022	RCV003224088.8
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely Benign (May 12, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280952.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Familial Cold Autoinflammatory Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000356923.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (2) PubMed: 11687797‚ 17393462
Likely benign (Apr 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cold urticaria Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000930272.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019	Geographic origin: Iran
Likely benign (Apr 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	DEAFNESS, AUTOSOMAL DOMINANT 34, WITH OR WITHOUT INFLAMMATION Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000930273.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019	Geographic origin: Iran
Likely benign (Feb 10, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966485.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (17) PubMed: 17213252‚ 25596455‚ 24123366‚ 11687797‚ 25038238‚ 28692792‚ 14872505‚ 26531310‚ 20159265‚ 23421920‚ 26020059‚ 12355493‚ 49161‚ 27994174‚ 17038455‚ 24135410‚ 22566169 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 4
Uncertain significance (Jan 10, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490471.2 First in ClinVar: Oct 02, 2016 Last updated: Apr 17, 2019	Comment: 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 … (more) 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) (less)
Uncertain significance (Apr 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002542638.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Uncertain significance (Dec 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Kidney disorder Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002587730.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Familial cold autoinflammatory syndrome 1 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV001135610.2 First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023
Uncertain significance (Oct 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715676.3 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Comment: BS1, BS2, BP4, PS4 Number of individuals with the variant: 13
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cryopyrin associated periodic syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000646274.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Uncertain significance (Nov 10, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604557.8 First in ClinVar: Oct 02, 2016 Last updated: Feb 20, 2024	Comment: 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% … (more) 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. (less)
Likely benign (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000891898.27 First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024	Comment: NLRP3: BP4, BS2 Number of individuals with the variant: 32
Uncertain significance (Feb 13, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Chronic infantile neurological, cutaneous and articular syndrome Familial cold autoinflammatory syndrome 1 Familial amyloid nephropathy with urticaria AND deafness Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000898853.2 First in ClinVar: Apr 25, 2019 Last updated: Jan 07, 2021	Comment: 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 … (more) 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. (less)
Uncertain significance (Jul 10, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475324.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (19) PubMed: 25038238‚ 17038455‚ 11687797‚ 12355493‚ 11992256‚ 15593220‚ 17393462‚ 24135410‚ 26020059‚ 23421920‚ 25596455‚ 27994174‚ 20159265‚ 28692792‚ 22566169‚ 29922587‚ 29159471‚ 30808881‚ 30407166
Uncertain significance (Oct 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Chronic infantile neurological, cutaneous and articular syndrome Familial cold autoinflammatory syndrome 1 Keratitis fugax hereditaria Hearing loss, autosomal dominant 34, with or without inflammation Familial amyloid nephropathy with urticaria AND deafness Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920290.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Nov 01, 2001)	no assertion criteria provided Method: literature only	FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024793.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016	Publications: PubMed (2) PubMed: 49161‚ 11687797 Comment on evidence: In a family with familial cold autoinflammatory syndrome (FCAS1; 120100) previously reported by Vlagopoulos et al. (1975), Hoffman et al. (2001) identified a G-to-A transition … (more) In a family with familial cold autoinflammatory syndrome (FCAS1; 120100) previously reported by Vlagopoulos et al. (1975), Hoffman et al. (2001) identified a G-to-A transition at nucleotide 592 in exon 3 of the CIAS1 gene, resulting in a valine-to-methionine substitution at codon 198 (V198M). (less)
Likely benign (Sep 16, 2019)	no assertion criteria provided Method: clinical testing	NLRP3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000310710.3 First in ClinVar: Oct 02, 2016 Last updated: Oct 08, 2024	Comment: 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).
not provided (-)	no classification provided Method: not provided	Familial cold urticaria Affected status: not provided Allele origin: unknown	Unité médicale des maladies autoinflammatoires, CHRU Montpellier Accession: SCV000116361.1 First in ClinVar: Mar 06, 2014 Last updated: Mar 06, 2014 Comment: also involved in OMIM 191900 and 607115
not provided (-)	no classification provided Method: phenotyping only	Chronic infantile neurological, cutaneous and articular syndrome Familial amyloid nephropathy with urticaria AND deafness Familial cold autoinflammatory syndrome 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown, maternal	GenomeConnect, ClinGen Accession: SCV000607138.2 First in ClinVar: Oct 16, 2017 Last updated: Jun 17, 2024	Comment: 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 … (more) 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. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Tinnitus (present) , Hearing impairment (present) , Short attention span (present) , Depression (present) , Anxiety (present) , Hyperhidrosis (present) , Hypopigmentation of the skin … (more) Tinnitus (present) , Hearing impairment (present) , Short attention span (present) , Depression (present) , Anxiety (present) , Hyperhidrosis (present) , Hypopigmentation of the skin (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the limbs (present) , EMG abnormality (present) , Abnormality of muscle physiology (present) , Hypercholesterolemia (present) , Hypertension (present) , Abnormality of urine homeostasis (present) , Abnormality of the female genitalia (present) , Recurrent infections (present) , Abnormal inflammatory response (present) (less) Indication for testing: Diagnostic Age: 50-59 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2015-09-09 Testing laboratory interpretation: Uncertain significance Observation 2: Number of individuals with the variant: 1 Clinical Features: Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) … (more) Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) , Obesity (present) , Overgrowth (present) , Abnormality of the parathyroid physiology (present) , Hyperthyroidism (present) , Goiter (present) , Adrenal hyperplasia (present) , Hypogonadism (present) , Precocious puberty (present) , Diabetes insipidus (present) , Delayed puberty (present) , Type I diabetes mellitus (present) , Type II diabetes mellitus (present) , Oral-pharyngeal dysphagia (present) , Abnormality of the neck (present) , Abnormality of the mouth (present) , Abnormality of the oral cavity (present) , Abnormality of the optic nerve (present) , Hypermetropia (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of eye movement (present) , Vertigo (present) , Tinnitus (present) , Sensorineural hearing impairment (present) , Abnormality of movement (present) , Memory impairment (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Anxiety (present) , Autistic behavior (present) , Hyperpigmentation of the skin (present) , Multiple cafe-au-lait spots (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of muscle physiology (present) , Hypercholesterolemia (present) , Hypertension (present) , Abnormality of cardiovascular system morphology (present) , Syncope (present) , Cardiomyopathy (present) , Abnormal EKG (present) , Arrhythmia (present) , Asthma (present) , Abnormality of the intestine (present) , Gastrointestinal dysmotility (present) , Abnormality of the liver (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Feeding difficulties (present) , Abnormality of urine homeostasis (present) , Abnormal renal morphology (present) , Abnormality of the bladder (present) , Rheumatoid arthritis (present) , Recurrent infections (present) , Abnormal inflammatory response (present) , Autoimmunity (present) , Abnormality of leukocytes (present) , Abnormality of erythrocytes (present) , Bleeding with minor or no trauma (present) , Abnormality of blood and blood-forming tissues (present) (less) Indication for testing: Diagnostic Age: 40-49 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2016-09-09 Testing laboratory interpretation: Uncertain significance
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Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Behçet's disease and genetic interactions between HLA-B*51 and variants in genes of autoinflammatory syndromes.	Burillo-Sanz S	Scientific reports	2019	PMID: 30808881
Novel presentations of periodic fever syndromes: Discrepancies between genetic and clinical diagnoses.	Hoang TK	European journal of rheumatology	2019	PMID: 30407166
De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome.	Torres A	Molecular genetics and metabolism reports	2018	PMID: 29922587
Evidence for genetic overlap between adult onset Still's disease and hereditary periodic fever syndromes.	Sighart R	Rheumatology international	2018	PMID: 29159471
Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges.	Kuemmerle-Deschner JB	Arthritis & rheumatology (Hoboken, N.J.)	2017	PMID: 28692792
Evidence of digenic inheritance in autoinflammation-associated genes.	Neocleous V	Journal of genetics	2016	PMID: 27994174
Early detection of sensorineural hearing loss in Muckle-Wells-syndrome.	Kuemmerle-Deschner JB	Pediatric rheumatology online journal	2015	PMID: 26531310
Expanding spectrum of neurologic manifestations in patients with NLRP3 low-penetrance mutations.	Schuh E	Neurology(R) neuroimmunology & neuroinflammation	2015	PMID: 26020059
A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants.	Rieber N	Clinical immunology (Orlando, Fla.)	2015	PMID: 25596455
Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.	Levy R	Annals of the rheumatic diseases	2015	PMID: 25038238
Novel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behçet's syndrome patients.	Yüksel Ş	International immunology	2014	PMID: 24135410
Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar.	Rodriguez-Flores JL	Human mutation	2014	PMID: 24123366
Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature.	Rowczenio DM	Arthritis research & therapy	2013	PMID: 23421920
Hereditary autoinflammatory syndromes: a Brazilian multicenter study.	Jesus AA	Journal of clinical immunology	2012	PMID: 22566169
Genetic predisposition (NLRP3 V198M mutation) for IL-1-mediated inflammation in a patient with Schnitzler syndrome.	Loock J	The Journal of allergy and clinical immunology	2010	PMID: 20159265
The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model.	Aksentijevich I	Arthritis and rheumatism	2007	PMID: 17393462
Autoinflammatory gene mutations in Behçet's disease.	Koné-Paut I	Annals of the rheumatic diseases	2007	PMID: 17213252
Refractory auto-inflammatory syndrome associated with digenic transmission of low-penetrance tumour necrosis factor receptor-associated periodic syndrome and cryopyrin-associated periodic syndrome mutations.	Touitou I	Annals of the rheumatic diseases	2006	PMID: 17038455
Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene.	Aróstegui JI	Arthritis and rheumatism	2004	PMID: 15593220
Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra.	Hawkins PN	Arthritis and rheumatism	2004	PMID: 14872505
Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis.	Aganna E	Arthritis and rheumatism	2002	PMID: 12355493
New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes.	Dodé C	American journal of human genetics	2002	PMID: 11992256
Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome.	Hoffman HM	Nature genetics	2001	PMID: 11687797
Familial cold urticaria.	Vlagopoulos T	Annals of allergy	1975	PMID: 49161
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Text-mined citations for rs121908147 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908147 ...