NM_001243133.2(NLRP3):c.1976T>G (p.Met659Arg) AND Cryopyrin associated periodic syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000796758.7

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1976T>G (p.Met659Arg)]

NM_001243133.2(NLRP3):c.1976T>G (p.Met659Arg)

Gene:

NLRP3:NLR family pyrin domain containing 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q44

Genomic location:

Preferred name:

NM_001243133.2(NLRP3):c.1976T>G (p.Met659Arg)

HGVS:

NC_000001.11:g.247425425T>G
NG_007509.2:g.14253T>G
NM_001079821.3:c.1976T>G
NM_001127461.3:c.1976T>G
NM_001127462.3:c.1976T>G
NM_001243133.2:c.1976T>GMANE SELECT
NM_004895.5:c.1982T>G
NM_183395.3:c.1976T>G
NP_001073289.2:p.Met659Arg
NP_001120933.2:p.Met659Arg
NP_001120934.2:p.Met659Arg
NP_001230062.1:p.Met659Arg
NP_004886.3:p.Met661Arg
NP_004886.3:p.Met661Arg
NP_899632.2:p.Met659Arg
LRG_197t1:c.1982T>G
LRG_197:g.14253T>G
LRG_197p1:p.Met661Arg
NC_000001.10:g.247588727T>G
NM_004895.4:c.1982T>G

Protein change:

M659R

Links:

dbSNP: rs180177457

NCBI 1000 Genomes Browser:

rs180177457

Molecular consequence:

NM_001079821.3:c.1976T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1976T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1976T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1976T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1982T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1976T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cryopyrin associated periodic syndrome (CAPS)
Identifiers:: MONDO: MONDO:0016168; MedGen: C2316212

Recent activity

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kynurenine--oxoglutarate transaminase 3 isoform 2 [Mus musculus]
kynurenine--oxoglutarate transaminase 3 isoform 2 [Mus musculus]
gi|30424613|ref|NP_776124.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000936284	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16081838, 24773462, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000936284

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 23, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients.

Stack JH, Beaumont K, Larsen PD, Straley KS, Henkel GW, Randle JC, Hoffman HM.

J Immunol. 2005 Aug 15;175(4):2630-4.

PubMed [citation]

PMID:: 16081838

Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS).

Haverkamp MH, van de Vosse E, Goldbach-Mansky R, Holland SM.

Clin Exp Immunol. 2014 Sep;177(3):720-31. doi: 10.1111/cei.12361.

PubMed [citation]

PMID:: 24773462
PMCID:: PMC4137857

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000936284.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met661 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 16081838, 24773462), 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. ClinVar contains an entry for this variant (Variation ID: 643124). This missense change has been observed in individuals with clinical features of cryopyrin-associated periodic syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 661 of the NLRP3 protein (p.Met661Arg).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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