rs121908150

Positions:

• chr1-247424227-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001243133.2(NLRP3):​c.778C>T​(p.Arg260Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NLRP3 NM_001243133.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 0.409

Genes affected

NLRP3 (HGNC:16400): (NLR family pyrin domain containing 3) This gene encodes a pyrin-like protein containing a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NLRP3 inflammasome complex. This complex functions as an upstream activator of NF-kappaB signaling, and it plays a role in the regulation of inflammation, the immune response, and apoptosis. The SARS-CoV 3a protein, a transmembrane pore-forming viroporin, has been shown to activate the NLRP3 inflammasome via the formation of ion channels in macrophages. Mutations in this gene are associated with familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), keratoendotheliitis fugax hereditarian, and deafness, autosomal dominant 34, with or without inflammation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Alternative 5' UTR structures are suggested by available data; however, insufficient evidence is available to determine if all of the represented 5' UTR splice patterns are biologically valid. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-247424227-C-T is Pathogenic according to our data. Variant chr1-247424227-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424227-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.778C>T	p.Arg260Ter	stop_gained	4/10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.778C>T	p.Arg260Ter	stop_gained	4/10	1	NM_001243133.2	ENSP00000337383	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 59 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as p.(R260W); This variant is associated with the following publications: (PMID: 26931528, 29331074, 29196621, 28569730, 20472245, 25596455, 17178985, 24501247, 11992256, 29773275, 28716882, 19302049, 23703389, 15020601, 31086329) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2019	The NLRP3 c.784C>T; p.Arg262Trp variant (rs121908150), also known as R260W in traditional nomenclature, is reported in the literature in multiple individuals and segregates with disease in families affected with cryopyrin-associated periodic syndrome (CAPS) (Alejandre 2014, Dode 2002, Lepore 2010, Parker 2016, Rieber 2015). This variant is reported in ClinVar (Variation ID: 4374), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 262 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate defects in inflammasome activation (Rieber 2015). Additionally, other variants at this codon (c.785G>T, p.Arg262Leu; c.785G>C, p.Arg262Pro) have been reported in individuals with CAPS (Neven 2004). Based on available information, this variant is considered to be pathogenic. References: Alejandre N et al. Description of a new family with cryopyrin-associated periodic syndrome: risk of visual loss in patients bearing the R260W mutation. Rheumatology (Oxford). 2014 Jun;53(6):1095-9. Dode C et al. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet. 2002 Jun;70(6):1498-506. Lepore L et al. Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with Anakinra. J Pediatr. 2010 Aug;157(2):310-315.e1. Neven B et al. Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood. 2004 Apr 1;103(7):2809-15. Parker T et al. Neurology of the cryopyrin-associated periodic fever syndrome. Eur J Neurol. 2016 Jul;23(7):1145-51. Rieber N et al. A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants. Clin Immunol. 2015 Mar;157(1):56-64. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 14, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial cold autoinflammatory syndrome 1 Pathogenic:1 Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2002	- -

Cryopyrin associated periodic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 262 of the NLRP3 protein (p.Arg262Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cryopyrin-associated periodic syndromes (CAPS) (PMID: 11992256, 20472245). It has also been observed to segregate with disease in related individuals. This variant is also known as R260W. The NLRP3 gene is also known as CIAS1 in the literature. ClinVar contains an entry for this variant (Variation ID: 4374). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 15020601, 23703389). For these reasons, this variant has been classified as Pathogenic. -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 26, 2021

- -

Familial amyloid nephropathy with urticaria AND deafness Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.48	N
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.86
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908150; hg19: chr1-247587529; COSMIC: COSV60220144;