rs28937896

Positions:

• chr1-247424507-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001243133.2(NLRP3):​c.1058T>C​(p.Leu353Pro) variant causes a missense change. 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. L353L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 4.18

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 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001243133.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NLRP3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 1-247424507-T-C is Pathogenic according to our data. Variant chr1-247424507-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-247424507-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP3	NM_001243133.2	c.1058T>C	p.Leu353Pro	missense_variant	4/10	ENST00000336119.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP3	ENST00000336119.8	c.1058T>C	p.Leu353Pro	missense_variant	4/10	1	NM_001243133.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Feb 01, 2003	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 05, 2019

The NLRP3 c.1064T>C; p.Leu355Pro variant (rs28937896), also known as p.Leu353Pro using traditional nomenclature, is reported in the literature in multiple individuals and families affected with familial cold autoinflammatory syndrome or Muckle-Wells syndrome (Hoffman 2003, Tran 2012). In three families, this variant occurred within a haplotype that co-segregated with disease in multiple affected individuals and was absent from unaffected relative (Hoffman 2003). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 355 is highly conserved, computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and it occurs in the functionally important NACHT nucleotide hydrolase domain adjacent to other disease-associated missense variants reported in the Human Gene Mutation Database (Stenson 2014). Additionally, a genetic mouse model carrying a heterozygous variant orthologous to p.Leu355Pro exhibits neonatal lethality attributed to hyperactive immune signaling (Brydges 2009). Based on available information, the p.Leu355Pro variant is considered to be pathogenic. References: Brydges SD et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity. 2009 Jun 19;30(6):875-87. Hoffman HM et al. Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P. Hum Genet. 2003 Feb;112(2):209-16. Stenson PD et al. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014 Jan;133(1):1-9. Tran TA et al. Muckle-Wells syndrome and male hypofertility: a case series. Semin Arthritis Rheum. 2012 Dec;42(3):327-31. -

Cryopyrin associated periodic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 355 of the NLRP3 protein (p.Leu355Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial cold autoinflammatory syndrome (FCAS) and FCAS and Muckle-Wells syndrome (PMID: 12522564, 16081838, 17393462, 21109514, 22512814, 22661645, 24773462). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4379). 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) performed at Invitae indicates that this missense variant is expected to disrupt NLRP3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 19501000, 28692792). For these reasons, this variant has been classified as Pathogenic. -

Familial amyloid nephropathy with urticaria AND deafness;C0409818:Chronic infantile neurological, cutaneous and articular syndrome;C1835697:Keratitis fugax hereditaria;C4521680:Hearing loss, autosomal dominant 34, with or without inflammation;C4551895:Familial cold autoinflammatory syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2018

The L355P missense variant in the NLRP3 gene has been previously reported in association with NLRP3-related disorders (Hoffman et al. 2003; Tran et al., 2012); therefore, this result is consistent with a diagnosis of a cryopyrin-associated disease . The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. L355P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the NACHT domain that is conserved in mammals, and where gain-of-function variants are known to cause NLRP3-related disorders (Lamkanfi et al., 2010). Missense variants in nearby residues (T350M, V353L/M, A354V, E356D, K357T/N, H360R) have been reported in the Human Gene Mutation Database in association with NLRP3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;.;.;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0050	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;.;D
Polyphen		1.0	D;D;D;D;D;.;.;P
Vest4		0.95
MutPred		0.79		Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);
MVP		0.96
MPC		1.7
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.94
gMVP		0.97

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: rs28937896; hg19: chr1-247587809;