NM_001243133.2(NLRP3):c.1217T>C (p.Met406Thr) AND Cryopyrin associated periodic syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 25, 2022
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:: RCV001053828.6

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1217T>C (p.Met406Thr)]

NM_001243133.2(NLRP3):c.1217T>C (p.Met406Thr)

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.1217T>C (p.Met406Thr)

HGVS:

NC_000001.11:g.247424666T>C
NG_007509.2:g.13494T>C
NM_001079821.3:c.1217T>C
NM_001127461.3:c.1217T>C
NM_001127462.3:c.1217T>C
NM_001243133.2:c.1217T>CMANE SELECT
NM_004895.5:c.1223T>C
NM_183395.3:c.1217T>C
NP_001073289.2:p.Met406Thr
NP_001120933.2:p.Met406Thr
NP_001120934.2:p.Met406Thr
NP_001230062.1:p.Met406Thr
NP_004886.3:p.Met408Thr
NP_899632.2:p.Met406Thr
LRG_197t1:c.1223T>C
LRG_197:g.13494T>C
NC_000001.10:g.247587968T>C
NM_004895.4:c.1223T>C

Protein change:

M406T

Links:

dbSNP: rs1662731815

NCBI 1000 Genomes Browser:

rs1662731815

Molecular consequence:

NM_001079821.3:c.1217T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1217T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1217T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1217T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1223T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1217T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001218110	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 25, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16920754, 21702021, 33020839, 34868041, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001218110

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 25, 2022)

germline

clinical testing

PubMed (5)
[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

Clinical and genetic characterization of Italian patients affected by CINCA syndrome.

Caroli F, Pontillo A, D'Osualdo A, Travan L, Ceccherini I, Crovella S, Alessio M, Stabile A, Gattorno M, Tommasini A, Martini A, Lepore L.

Rheumatology (Oxford). 2007 Mar;46(3):473-8. Epub 2006 Aug 18.

PubMed [citation]

PMID:: 16920754

High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study.

Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, Nishikomori R, Morimoto T, Kambe N, Goldbach-Mansky R, Aksentijevich I, de Saint Basile G, Neven B, van Gijn M, Frenkel J, Aróstegui JI, Yagüe J, Merino R, Ibañez M, Pontillo A, Takada H, Imagawa T, et al.

Arthritis Rheum. 2011 Nov;63(11):3625-32. doi: 10.1002/art.30512.

PubMed [citation]

PMID:: 21702021
PMCID:: PMC3498501

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001218110.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant disrupts the p.Met408 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 16920754, 21702021), 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: 849794). This variant is also known as c.1217T>C (p.Met406Thr). This missense change has been observed in individual(s) with clinical features of cryopyrin-associated periodic syndrome and/or neonatal multisystem onset inflammatory disorder (PMID: 33020839, 34868041; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 408 of the NLRP3 protein (p.Met408Thr). For these reasons, this variant has been classified as Pathogenic.

#	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: Feb 20, 2024

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