NM_001243133.2(NLRP3):c.1218G>A (p.Met406Ile) AND Cryopyrin associated periodic syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 28, 2020
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:: RCV001377285.6

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1218G>A (p.Met406Ile)]

NM_001243133.2(NLRP3):c.1218G>A (p.Met406Ile)

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.1218G>A (p.Met406Ile)

HGVS:

NC_000001.11:g.247424667G>A
NG_007509.2:g.13495G>A
NM_001079821.3:c.1218G>A
NM_001127461.3:c.1218G>A
NM_001127462.3:c.1218G>A
NM_001243133.2:c.1218G>AMANE SELECT
NM_004895.5:c.1224G>A
NM_183395.3:c.1218G>A
NP_001073289.2:p.Met406Ile
NP_001120933.2:p.Met406Ile
NP_001120934.2:p.Met406Ile
NP_001230062.1:p.Met406Ile
NP_004886.3:p.Met408Ile
NP_899632.2:p.Met406Ile
LRG_197:g.13495G>A
NC_000001.10:g.247587969G>A

Protein change:

M406I

Links:

dbSNP: rs180177486

NCBI 1000 Genomes Browser:

rs180177486

Molecular consequence:

NM_001079821.3:c.1218G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1218G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1218G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1218G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1224G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1218G>A - 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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N-acetylneuraminic acid mutarotase [Brucella melitensis NI]
N-acetylneuraminic acid mutarotase [Brucella melitensis NI]
gi|349744543|gnl|cvmcau|BMNI_II0375 EQ10085.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001574573	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 28, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21702021, 16920754, 21637346, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001574573

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 28, 2020)

germline

clinical testing

PubMed (4)
[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

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

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

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001574573.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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.Met408 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been observed in individuals with NLRP3-related conditions (PMID: 21702021, Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with Cryopyrin-associated periodic syndrome (PMID: 16920754, 21637346). This variant is also known as M406I in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 408 of the NLRP3 protein (p.Met408Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine.

#	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: Mar 5, 2024

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