NM_001243133.2(NLRP3):c.1374C>A (p.His458Gln) AND Cryopyrin associated periodic syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 19, 2023
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:: RCV002012102.5

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1374C>A (p.His458Gln)]

NM_001243133.2(NLRP3):c.1374C>A (p.His458Gln)

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.1374C>A (p.His458Gln)

HGVS:

NC_000001.11:g.247424823C>A
NG_007509.2:g.13651C>A
NM_001079821.3:c.1374C>A
NM_001127461.3:c.1374C>A
NM_001127462.3:c.1374C>A
NM_001243133.2:c.1374C>AMANE SELECT
NM_004895.4:c.1380C>A
NM_004895.5:c.1380C>A
NM_183395.3:c.1374C>A
NP_001073289.2:p.His458Gln
NP_001120933.2:p.His458Gln
NP_001120934.2:p.His458Gln
NP_001230062.1:p.His458Gln
NP_004886.3:p.His460Gln
NP_899632.2:p.His458Gln
LRG_197t1:c.1380C>A
LRG_197:g.13651C>A
NC_000001.10:g.247588125C>A

Protein change:

H458Q

Links:

dbSNP: rs180177481

NCBI 1000 Genomes Browser:

rs180177481

Molecular consequence:

NM_001079821.3:c.1374C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1374C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1374C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1374C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1380C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1374C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Geoplana cytochrome oxidase subunit I (COI) gene, partial cds; mitochondrial.
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002220424	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002220424

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 19, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002220424.4

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

Description

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 460 of the NLRP3 protein (p.His460Gln). This variant is present in population databases (rs180177481, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NLRP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1448252). 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 not expected to disrupt NLRP3 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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