NM_001243133.2(NLRP3):c.1305G>C (p.Lys435Asn) AND Cryopyrin associated periodic syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 24, 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:: RCV003038211.3

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1305G>C (p.Lys435Asn)]

NM_001243133.2(NLRP3):c.1305G>C (p.Lys435Asn)

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.1305G>C (p.Lys435Asn)

HGVS:

NC_000001.11:g.247424754G>C
NG_007509.2:g.13582G>C
NM_001079821.3:c.1305G>C
NM_001127461.3:c.1305G>C
NM_001127462.3:c.1305G>C
NM_001243133.2:c.1305G>CMANE SELECT
NM_004895.5:c.1311G>C
NM_183395.3:c.1305G>C
NP_001073289.2:p.Lys435Asn
NP_001120933.2:p.Lys435Asn
NP_001120934.2:p.Lys435Asn
NP_001230062.1:p.Lys435Asn
NP_004886.3:p.Lys437Asn
NP_004886.3:p.Lys437Asn
NP_899632.2:p.Lys435Asn
LRG_197t1:c.1311G>C
LRG_197:g.13582G>C
LRG_197p1:p.Lys437Asn
NC_000001.10:g.247588056G>C
NM_004895.4:c.1311G>C

Protein change:

K435N

Molecular consequence:

NM_001079821.3:c.1305G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1305G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1305G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1305G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1311G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1305G>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
SCV003327332	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30273710, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003327332

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 24, 2023)

germline

clinical testing

PubMed (2)
[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

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases.

Mensa-Vilaró A, Bravo García-Morato M, de la Calle-Martin O, Franco-Jarava C, Martínez-Saavedra MT, González-Granado LI, González-Roca E, Fuster JL, Alsina L, Mutchinick OM, Balderrama-Rodríguez A, Ramos E, Modesto C, Mesa-Del-Castillo P, Ortego-Centeno N, Clemente D, Souto A, Palmou N, Remesal A, Leslie KS, Gómez de la Fuente E, Yadira Bravo Gallego L, et al.

J Allergy Clin Immunol. 2019 Jan;143(1):359-368. doi: 10.1016/j.jaci.2018.09.009. Epub 2018 Sep 29.

PubMed [citation]

PMID:: 30273710

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, SCV003327332.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 437 of the NLRP3 protein (p.Lys437Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Muckle-Wells syndrome (PMID: 30273710). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 2109144). 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 95%. 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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