1-247424756-C-T

Variant names:

• chr1-247424756-C-T
• rs180177433
• NM_001243133.2:c.1307C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001243133.2(NLRP3):​c.1307C>T​(p.Thr436Ile) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T436N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 4.27
• Publications: 16 publications found

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]

NLRP3 Gene-Disease associations (from GenCC):

• CINCA syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cryopyrin-associated periodic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• familial cold autoinflammatory syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• familial cold autoinflammatory syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Muckle-Wells syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• keratitis fugax hereditaria

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 19 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, 8 uncertain in NM_001243133.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-247424755-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97921.
• PP2: Missense variant in the NLRP3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.1417 (below the threshold of 3.09). Trascript score misZ: 3.5037 (above the threshold of 3.09). GenCC associations: The gene is linked to CINCA syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome 1, familial cold autoinflammatory syndrome, cryopyrin-associated periodic syndrome, keratitis fugax hereditaria.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 1-247424756-C-T is Pathogenic according to our data. Variant chr1-247424756-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 97924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.1307C>T	p.Thr436Ile	missense_variant	Exon 4 of 10	ENST00000336119.8	NP_001230062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP3	ENST00000336119.8	c.1307C>T	p.Thr436Ile	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cryopyrin associated periodic syndrome Pathogenic:1

Sep 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 97924). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr438 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 12032915, 17513575, 25979514, 26245507, 27191192), which suggests that this may be a clinically significant amino acid residue. 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. This variant is also known as 1307C>T and T436I. This missense change has been observed in individuals with cryopyrin-associated periodic syndromes (CAPS) (PMID: 18080732, 26931528, 28501347, 29047407, 29988644). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 438 of the NLRP3 protein (p.Thr438Ile). -

not provided Pathogenic:1

Apr 29, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NLRP3 c.1313C>T; p.Thr438Ile variant (rs180177433), also published as Thr346Ile, is reported in the literature in several unrelated individuals affected with CAPS (Chan 2018, Jesus 2008, Munoz 2017, Neven 2004, Papa 2017). This variant is reported in ClinVar (Variation ID: 97924) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 438 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.759). Additionally, other variants in the same codon (p.Thr438Ala, p.Thr348Asn) have also been reported in affected individuals (Feldmann 2002, Zeft 2007). Based on available information, this variant is classified as likely pathogenic. References: Chan L et al. Erythema nodosum in an adolescent patient with cryopyrin-associated periodic syndrome. Clin Case Rep. 2018 May 15;6(7):1241-1245. PMID: 29988644. Feldmann J et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002 Jul;71(1):198-203. PMID: 12032915. Jesus AA et al. Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): description of a rare non-exon 3 and a novel CIAS1 missense mutation. J Clin Immunol. 2008 Mar;28(2):134-8. PMID: 18080732. Munoz MA et al. Defective protein prenylation is a diagnostic biomarker of mevalonate kinase deficiency. J Allergy Clin Immunol. 2017 Sep;140(3):873-875.e6. PMID: 28501347. 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. PMID: 14630794. Papa R et al. A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet J Rare Dis. 2017 Oct 18;12(1):167. PMID: 29047407. Zeft A and Bohnsack JF. Cryopyrin-associated autoinflammatory syndrome: a new mutation. Ann Rheum Dis. 2007 Jun;66(6):843-4. PMID: 17513575. -

Familial cold autoinflammatory syndrome 1 Other:1

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;.;D;D;.;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
PhyloP100		4.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;.;.;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;D
Polyphen		1.0	D;D;D;D;D;.;.;D
Vest4		0.89
MutPred		0.88		Loss of disorder (P = 0.026);Loss of disorder (P = 0.026);Loss of disorder (P = 0.026);Loss of disorder (P = 0.026);Loss of disorder (P = 0.026);Loss of disorder (P = 0.026);Loss of disorder (P = 0.026);Loss of disorder (P = 0.026);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.77
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs180177433; hg19: chr1-247588058;