1-247424356-G-C

Variant names:

• chr1-247424356-G-C
• rs121908153
• NM_001243133.2:c.907G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001243133.2(NLRP3):​c.907G>C​(p.Asp303His) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D303N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP3 NM_001243133.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.13
• Publications: 100 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 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr1-247424356-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.986
• PP5: Variant 1-247424356-G-C is Pathogenic according to our data. Variant chr1-247424356-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97979.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP3	NM_001243133.2	c.907G>C	p.Asp303His	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.907G>C	p.Asp303His	missense_variant	Exon 4 of 10	1	NM_001243133.2	ENSP00000337383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cryopyrin associated periodic syndrome Pathogenic:1

Feb 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 305 of the NLRP3 protein (p.Asp305His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with chronic infantile neurological, cutaneous, and articular syndrome or neonatal onset multisystem inflammatory disease (PMID: 18084703, 21702021). This variant is also known as D303H. ClinVar contains an entry for this variant (Variation ID: 97979). 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 95%. This variant disrupts the p.Asp305 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14630794, 33020839, 34099780). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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	0.92
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;D;D;.;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;.;T;T;.;T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
PhyloP100		7.1
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;.;.;D
REVEL	Pathogenic	0.82
Sift	Benign	0.034	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.041	D;D;D;D;D;.;.;D
Polyphen		1.0	D;D;D;D;D;.;.;D
Vest4		0.93
MutPred		0.94		Gain of catalytic residue at L307 (P = 0.091);Gain of catalytic residue at L307 (P = 0.091);Gain of catalytic residue at L307 (P = 0.091);Gain of catalytic residue at L307 (P = 0.091);Gain of catalytic residue at L307 (P = 0.091);Gain of catalytic residue at L307 (P = 0.091);Gain of catalytic residue at L307 (P = 0.091);Gain of catalytic residue at L307 (P = 0.091);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.66
gMVP		0.92
Mutation Taster		=0/100	disease causing

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: rs121908153; hg19: chr1-247587658;