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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:
RCV001053828.7

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001218110Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jul 25, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001218110.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024