NM_001243133.2(NLRP3):c.1058T>C (p.Leu353Pro) AND Cryopyrin associated periodic syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 29, 2024
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:: RCV000795773.7

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1058T>C (p.Leu353Pro)]

NM_001243133.2(NLRP3):c.1058T>C (p.Leu353Pro)

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.1058T>C (p.Leu353Pro)

HGVS:

NC_000001.11:g.247424507T>C
NG_007509.2:g.13335T>C
NM_001079821.3:c.1058T>C
NM_001127461.3:c.1058T>C
NM_001127462.3:c.1058T>C
NM_001243133.2:c.1058T>CMANE SELECT
NM_004895.5:c.1064T>C
NM_183395.3:c.1058T>C
NP_001073289.2:p.Leu353Pro
NP_001120933.2:p.Leu353Pro
NP_001120934.2:p.Leu353Pro
NP_001230062.1:p.Leu353Pro
NP_001230062.1:p.Leu353Pro
NP_004886.3:p.Leu355Pro
NP_004886.3:p.Leu355Pro
NP_899632.2:p.Leu353Pro
LRG_197t1:c.1064T>C
LRG_197:g.13335T>C
LRG_197p1:p.Leu355Pro
NC_000001.10:g.247587809T>C
NM_001243133.1:c.1058T>C
NM_004895.4:c.1064T>C

Protein change:

L353P; LEU353PRO

Links:

OMIM: 606416.0010; dbSNP: rs28937896

NCBI 1000 Genomes Browser:

rs28937896

Molecular consequence:

NM_001079821.3:c.1058T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1058T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1058T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1058T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1064T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1058T>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
SCV000935247	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 12522564, 16081838, 17393462, 21109514, 22512814, 22661645, 24773462, 19501000, 28692792, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000935247

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (10)
[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

Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P.

Hoffman HM, Gregory SG, Mueller JL, Tresierras M, Broide DH, Wanderer AA, Kolodner RD.

Hum Genet. 2003 Feb;112(2):209-16. Epub 2002 Nov 16.

PubMed [citation]

PMID:: 12522564

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

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000935247.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 355 of the NLRP3 protein (p.Leu355Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial cold autoinflammatory syndrome (FCAS) and FCAS and Muckle-Wells syndrome (PMID: 12522564, 16081838, 17393462, 21109514, 22512814, 22661645, 24773462). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4379). 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 80%. Experimental studies have shown that this missense change affects NLRP3 function (PMID: 19501000, 28692792). 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: Sep 29, 2024

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