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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002570248Johns Hopkins Genomics, Johns Hopkins University
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jun 1, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024