NM_001243133.2(NLRP3):c.2107C>A (p.Gln703Lys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Nov 17, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000416176.44

Allele description [Variation Report for NM_001243133.2(NLRP3):c.2107C>A (p.Gln703Lys)]

NM_001243133.2(NLRP3):c.2107C>A (p.Gln703Lys)

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.2107C>A (p.Gln703Lys)

HGVS:

NC_000001.11:g.247425556C>A
NG_007509.2:g.14384C>A
NM_001079821.3:c.2107C>A
NM_001127461.3:c.2107C>A
NM_001127462.3:c.2107C>A
NM_001243133.2:c.2107C>AMANE SELECT
NM_004895.5:c.2113C>A
NM_183395.3:c.2107C>A
NP_001073289.1:p.Gln705Lys
NP_001073289.2:p.Gln703Lys
NP_001120933.2:p.Gln703Lys
NP_001120934.2:p.Gln703Lys
NP_001230062.1:p.Gln703Lys
NP_004886.3:p.Gln705Lys
NP_004886.3:p.Gln705Lys
NP_899632.2:p.Gln703Lys
LRG_197t1:c.2113C>A
LRG_197:g.14384C>A
LRG_197p1:p.Gln705Lys
NC_000001.10:g.247588858C>A
NM_001079821.2:c.2113C>A
NM_004895.4:c.2113C>A
Q96P20:p.Gln705Lys

Protein change:

Q703K

Links:

UniProtKB: Q96P20#VAR_043693; dbSNP: rs35829419

NCBI 1000 Genomes Browser:

rs35829419

Molecular consequence:

NM_001079821.3:c.2107C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.2107C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.2107C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.2107C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.2113C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.2107C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000493426	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Benign (Mar 1, 2022)	germline	clinical testing	Citation Link,
SCV000604550	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Benign (Nov 17, 2023)	germline	clinical testing	Citation Link,
SCV001144770	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics Criteria)	Benign (Dec 31, 2018)	germline	clinical testing	PubMed (34) [See all records that cite these PMIDs] 22529966, 28185410, 24649046, 26535712, 21245836, 26178285, 27060062, 28137891, 26020059, 22128899, 21621776, 22843550, 26273672, 22524199, 24158955, 25586466, 26033552, 24098386, 17509468, 22403613, 26848126, 29977033, 28692792, 29148409, 27943647, 27036377, 25596455, 20182451, 19319132, 18311798, 22935299, 28028683, 24431285, 26467025
SCV001752083	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Benign (Jan 16, 2019)	germline	clinical testing	Citation Link,
SCV002036408	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV002568170	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 1, 2022)	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	yes	7	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and IL-18 production.

Verma D, Särndahl E, Andersson H, Eriksson P, Fredrikson M, Jönsson JI, Lerm M, Söderkvist P.

PLoS One. 2012;7(4):e34977. doi: 10.1371/journal.pone.0034977. Epub 2012 Apr 17.

PubMed [citation]

PMID:: 22529966
PMCID:: PMC3328489

NLRP3 p.Q705K and CARD8 p.C10X single nucleotide polymorphisms are not associated with susceptibility to rheumatoid arthritis: a meta-analysis.

Yang Z, Cao J, Yang Q, Zhang Y, Han L.

Int J Rheum Dis. 2017 Oct;20(10):1481-1491. doi: 10.1111/1756-185X.13016. Epub 2017 Feb 9. Review.

PubMed [citation]

PMID:: 28185410

See all PubMed Citations (35)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV000493426.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		7	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604550.10

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

#	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

From Athena Diagnostics Inc, SCV001144770.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (34)

#	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

From GeneDx, SCV001752083.1

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32477355, 26178285, 32199921, 22843550, 30245029, 29148409, 28638818, 28692792, 29977033, 29265930, 30140708, 29610014, 27576327, 29770580, 23215645, 29850521, 29230505, 22128899, 17509468, 22529966, 28028683, 26020059, 27036377, 27943647, 26848126, 27884173, 22403613, 22995991, 20182451, 25596455, 22935299, 18311798, 21245836, 19319132, 20981092, 29097263, 29500522, 30447690, 30536174)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036408.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002568170.1

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

Description

PS3, BS1, BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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