NM_001243133.2(NLRP3):c.1568T>G (p.Phe523Cys) AND Cryopyrin associated periodic syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 3, 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:: RCV001382398.5

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1568T>G (p.Phe523Cys)]

NM_001243133.2(NLRP3):c.1568T>G (p.Phe523Cys)

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.1568T>G (p.Phe523Cys)

HGVS:

NC_000001.11:g.247425017T>G
NG_007509.2:g.13845T>G
NM_001079821.3:c.1568T>G
NM_001127461.3:c.1568T>G
NM_001127462.3:c.1568T>G
NM_001243133.2:c.1568T>GMANE SELECT
NM_004895.5:c.1574T>G
NM_183395.3:c.1568T>G
NP_001073289.2:p.Phe523Cys
NP_001120933.2:p.Phe523Cys
NP_001120934.2:p.Phe523Cys
NP_001230062.1:p.Phe523Cys
NP_001230062.1:p.Phe523Cys
NP_004886.3:p.Phe525Cys
NP_899632.2:p.Phe523Cys
LRG_197:g.13845T>G
NC_000001.10:g.247588319T>G
NM_001243133.1:c.1568T>G

Protein change:

F523C

Links:

dbSNP: rs180177478

NCBI 1000 Genomes Browser:

rs180177478

Molecular consequence:

NM_001079821.3:c.1568T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1568T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1568T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1568T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1574T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1568T>G - 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
SCV001581150	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 3, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17284928, 24773462, 26931528, 29047407, 12483741, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001581150

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 3, 2020)

germline

clinical testing

PubMed (6)
[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

A novel missense mutation in CIAS1 encoding the pyrin-like protein, cryopyrin, causes familial cold autoinflammatory syndrome in a family of Ethiopian origin.

Shalev SA, Sprecher E, Indelman M, Hujirat Y, Bergman R, Rottem M.

Int Arch Allergy Immunol. 2007;143(3):190-3. Epub 2007 Feb 6.

PubMed [citation]

PMID:: 17284928

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 (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001581150.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces phenylalanine with cysteine at codon 525 of the NLRP3 protein (p.Phe525Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of cryopyrin-associated periodic syndrome (CAPS) (PMID: 17284928, 24773462, 26931528, 29047407, Invitae). It has also been observed to segregate with disease in related individuals. In the literature, this gene is also known as CIAS1, and this variant is also known as F523C. ClinVar contains an entry for this variant (Variation ID: 97936). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Phe525 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12483741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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