rs151344629

Positions:

• chr1-247424492-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001243133.2(NLRP3):​c.1043C>T​(p.Thr348Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T348T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 2.71

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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001243133.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NLRP3. . Gene score misZ 2.1417 (greater than the threshold 3.09). Trascript score misZ 3.5037 (greater than threshold 3.09). GenCC has associacion of gene with familial cold autoinflammatory syndrome, keratitis fugax hereditaria, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, CINCA syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 1-247424492-C-T is Pathogenic according to our data. Variant chr1-247424492-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424492-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.1043C>T	p.Thr348Met	missense_variant	4/10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.1043C>T	p.Thr348Met	missense_variant	4/10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 24, 2018	The NLRP3 c.1049C>T;p.Thr350Met (rs151344629), also known as Thr348Met, is published in the literature in individuals with various periodic fever syndromes (Kuemmerle-Deschner 2011, Kuemmerle-Deschner 2015). The variant has been described both as occurring de novo and as segregating with disease (Dode 2002, Kanariou 2014). The variant is listed as pathogenic in the ClinVar database (Variation ID: 97909). The variant is not listed in the general population databases (Exome Variant Server, Exome Aggregation Consortium), indicating it is not a common polymorphism. The threonine at codon 350 is moderately conserved across a variety of species and computational programs (Align GVGD, SIFT) predict this variant is deleterious to protein function. Considering available information, this variant is classified as pathogenic. Pathogenic NLRP3 variants are causative for autosomal dominant Muckle-Wells syndrome (MIM#606416). References: 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 70(6):1498-506. Kanariou M et al. Successful management of cryopyrin-associated periodic syndrome with canakinumab in infancy. Pediatrics. 2014 134(5):e1468-73. Kuemmerle-Deschner JB et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1B mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther. 2011 13(1):R34. Kuemmerle-Deschner JB et al. Early detection of sensorineural hearing loss in Muckle-Wells-syndrome. Pediatr Rheumatol Online J. 2015 13(1):43. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	NLRP3: PP1:Strong, PM1, PM2, PS4:Moderate, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27435956, 14630794, 21356079, 26531310, 27353043, 23442610, 17178739, 25730877, 34979568, 31816408, 33042144, 20472245, 25349319, 24952504, 26931528, 11992256, 28028683, 28501347, 25596455, 16100350, 26245507, 30184330, 30273710, 23486414, 15593220, 32152129, 34099780) -

Cryopyrin associated periodic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 16100350, 25730877). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 97909). This variant is also known as p.Thr348Met. This missense change has been observed in individual(s) with clinical features of NLRP3-related conditions (PMID: 11992256, 16100350, 17178739, 20472245, 21356079, 23442610, 25730877, 26245507, 26531310, 26931528). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 350 of the NLRP3 protein (p.Thr350Met). -

Familial amyloid nephropathy with urticaria AND deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Aug 11, 2014

- -

Autoinflammatory syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 15, 2021

- -

Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Dec 07, 2022

- -

Familial cold autoinflammatory syndrome 1 Other:1

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;.;.;D
REVEL	Pathogenic	0.78
Sift	Benign	0.060	T;T;T;T;T;.;.;T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;.;D
Polyphen		1.0	D;D;D;D;D;.;.;D
Vest4		0.88
MutPred		0.76		Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);Loss of glycosylation at T350 (P = 0.157);
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.53
gMVP		0.80

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: rs151344629; hg19: chr1-247587794;