NM_001243133.2(NLRP3):c.1639A>T (p.Ser547Cys) AND Hearing loss, autosomal dominant 34, with or without inflammation

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 1, 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:: RCV002282291.1

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1639A>T (p.Ser547Cys)]

NM_001243133.2(NLRP3):c.1639A>T (p.Ser547Cys)

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.1639A>T (p.Ser547Cys)

HGVS:

NC_000001.11:g.247425088A>T
NG_007509.2:g.13916A>T
NM_001079821.3:c.1639A>T
NM_001127461.3:c.1639A>T
NM_001127462.3:c.1639A>T
NM_001243133.2:c.1639A>TMANE SELECT
NM_004895.5:c.1645A>T
NM_183395.3:c.1639A>T
NP_001073289.1:p.Ser549Cys
NP_001073289.2:p.Ser547Cys
NP_001120933.2:p.Ser547Cys
NP_001120934.2:p.Ser547Cys
NP_001230062.1:p.Ser547Cys
NP_004886.3:p.Ser549Cys
NP_004886.3:p.Ser549Cys
NP_899632.2:p.Ser547Cys
LRG_197t1:c.1645A>T
LRG_197:g.13916A>T
LRG_197p1:p.Ser549Cys
NC_000001.10:g.247588390A>T
NM_001079821.2:c.1645A>T
NM_004895.4:c.1645A>T
p.Ser549Cys

Protein change:

S547C

Links:

dbSNP: rs139833874

NCBI 1000 Genomes Browser:

rs139833874

Molecular consequence:

NM_001079821.3:c.1639A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1639A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1639A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1639A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1645A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1639A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hearing loss, autosomal dominant 34, with or without inflammation
Synonyms:: Deafness, autosomal dominant 34, with or without inflammation
Identifiers:: MONDO: MONDO:0033261; MedGen: C4521680; OMIM: 617772

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002570248	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 1, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27612399, 28692792, 33329557, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002570248

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 1, 2022)

germline

clinical testing

PubMed (4)
[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

Autoinflammatory associated vasculitis.

Ginsberg S, Rosner I, Rozenbaum M, Slobodin G, Zilber K, Boulman N, Kaly L, Awisat A, Jiries N, Beyar-Katz O, Rimar D.

Semin Arthritis Rheum. 2016 Dec;46(3):367-371. doi: 10.1016/j.semarthrit.2016.07.007. Epub 2016 Jul 20.

PubMed [citation]

PMID:: 27612399

Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges.

Kuemmerle-Deschner JB, Verma D, Endres T, Broderick L, de Jesus AA, Hofer F, Blank N, Krause K, Rietschel C, Horneff G, Aksentijevich I, Lohse P, Goldbach-Mansky R, Hoffman HM, Benseler SM.

Arthritis Rheumatol. 2017 Nov;69(11):2233-2240. doi: 10.1002/art.40208. Epub 2017 Oct 17.

PubMed [citation]

PMID:: 28692792

See all PubMed Citations (4)

Details of each submission

From Johns Hopkins Genomics, Johns Hopkins University, SCV002570248.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This NLRP3 variant (rs139833874) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African/African American subpopulation (gnomAD: 81/24950 alleles; 0.3%; no homozygotes). This patient's ethnicity is reported to be African American and Hispanic. This variant has been reported in ClinVar and in two meeting abstracts describing individuals with NLRP3-AID. This missense change affects a residue in the helical 2 (HD2) subdomain of the NLRP3 protein but does not occur in any known hotspot associated with NLRP3-AID. Three bioinformatic tools queried predict that the substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function variants. The serine residue at this position is conserved across primates, but weakly conserved across other vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 4 splicing, although this has not been confirmed experimentally to our knowledge. We consider the clinical significance of this variant to be uncertain at this time. knowledge. Due to insufficient evidence, we consider the clinical significance of c.1639A>T to be uncertain at this time.

#	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: Oct 13, 2024

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