VCV000446409.12 - ClinVar

NM_001243133.2(NLRP3):c.2753G>A (p.Arg918Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001243133.2(NLRP3):c.2753G>A (p.Arg918Gln)

Variation ID: 446409 Accession: VCV000446409.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q44 1: 247444061 (GRCh38) [ NCBI UCSC ] 1: 247607363 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 4, 2017	Feb 14, 2024	Dec 27, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001243133.2:c.2753G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230062.1:p.Arg918Gln	missense
NM_001079821.3:c.2753G>A	NP_001073289.2:p.Arg918Gln	missense
NM_001127461.3:c.2582G>A	NP_001120933.2:p.Arg861Gln	missense
NM_001127462.3:c.2582G>A	NP_001120934.2:p.Arg861Gln	missense
NM_004895.5:c.2759G>A	NP_004886.3:p.Arg920Gln	missense
NM_183395.3:c.2411G>A	NP_899632.2:p.Arg804Gln	missense
NC_000001.11:g.247444061G>A
NC_000001.10:g.247607363G>A
NG_007509.2:g.32889G>A
LRG_197:g.32889G>A
LRG_197t1:c.2759G>A	LRG_197p1:p.Arg920Gln

... more HGVS ... less HGVS

Protein change

R918Q, R920Q, R804Q, R861Q

Other names

Canonical SPDI

NC_000001.11:247444060:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA345565085 OMIM: 606416.0011 dbSNP: rs1553293095 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NLRP3		-	-	GRCh38 GRCh38 GRCh37	980	1063

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hearing loss, autosomal dominant 34, with or without inflammation	Pathogenic (1)	no assertion criteria provided	Nov 28, 2017	RCV000515640.1
Cryopyrin associated periodic syndrome	no classifications from unflagged records (1)	no classifications from unflagged records	Aug 5, 2024	RCV000693681.9
not provided	Likely pathogenic (1)	criteria provided, single submitter	Dec 27, 2021	RCV001591164.5
NLRP3-related disorder	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003335442.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Dec 27, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001824195.3 First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein … (more) Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.R918Q; This variant is associated with the following publications: (PMID: 33329557, 34671876, Broderick2015[MeetingAbstract], 29342053, 28847925) (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NLRP3-related disorder Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046331.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant has been previously reported as a heterozygous change in affected family members from two families with sensorineural hearing loss with and without systemic … (more) This variant has been previously reported as a heterozygous change in affected family members from two families with sensorineural hearing loss with and without systemic autoinflammation (PMID: 28847925, 29342053). Functional studies in cultured patient cells showed release of high levels of IL-1β in response to stimulation with LPS, supporting gain of function mechanism of the c.2759G>A (p.Arg920Gln) variant (PMID: 28847925, 29342053). This variant is absent from the gnomAD population database and thus is presumed to be rare. In silico analyses do not support a deleterious effect of the c.2759G>A (p.Arg920Gln) variant on protein function. Based on the available evidence, the c.2759G>A (p.Arg920Gln) variant is classified as Likely Pathogenic. (less)
Pathogenic (Nov 28, 2017)	no assertion criteria provided Method: literature only	DEAFNESS, AUTOSOMAL DOMINANT 34, WITH OR WITHOUT INFLAMMATION Affected status: not provided Allele origin: germline	OMIM Accession: SCV000611755.1 First in ClinVar: Dec 04, 2017 Last updated: Dec 04, 2017	Publications: PubMed (1) PubMed: 28847925 Comment on evidence: In affected members of 2 unrelated families from North America (families LMG113 and LMG446) with autosomal dominant deafness-34 with or without inflammation (DFNA34; 617772), Nakanishi … (more) In affected members of 2 unrelated families from North America (families LMG113 and LMG446) with autosomal dominant deafness-34 with or without inflammation (DFNA34; 617772), Nakanishi et al. (2017) identified a heterozygous c.2753G-A transition (c.2753G-A, NM_001243133.1) in exon 7 of the NLRP3 gene, resulting in an arg918-to-gln (R918Q) substitution at a conserved residue in the LRR domain. The mutation, which was found by linkage analysis followed by candidate gene sequencing in family LMG113, segregated with the disorder in both families. It was not found in the ExAC database (January 19, 2017) or in 572 control chromosomes. Haplotype analysis suggested a founder effect for the 2 families. Laboratory studies of affected individuals showed increased IL1B (147720) secretion in response to LPS stimulation and variably increased serologic markers of inflammation compared to controls, suggesting a gain-of-function effect. Direct functional studies of the variant were not performed. Patients also showed pathologic enhancement of the cochlea on imaging, suggesting cochlear autoinflammation. Family LMG113 did not show significant additional features of an inflammatory disorder, but affected members from family LMG446 did show such features, including periodic fevers, urticaria, lymphadenopathy, conjunctivitis, ulcers, and arthralgias. The findings broadened the phenotype associated with NLRP3 mutations. (less)
Uncertain significance (Jun 23, 2018)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Cryopyrin associated periodic syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000821559.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The … (more) Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces arginine with glutamine at codon 920 of the NLRP3 protein (p.Arg920Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate¬†in families¬†with cryopyrin-associated periodic syndromes (CAPS) and¬†autosomal dominant deafness-34 (DFNA34) (PMID:¬†28847925). This variant is also known as p.Arg918Gln in the literature. ClinVar contains an entry for this variant (Variation ID:¬†446409). 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. (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.R918Q; This variant is associated with the following publications: (PMID: 33329557, 34671876, Broderick2015[MeetingAbstract], 29342053, 28847925)

Comment:

This variant has been previously reported as a heterozygous change in affected family members from two families with sensorineural hearing loss with and without systemic autoinflammation (PMID: 28847925, 29342053). Functional studies in cultured patient cells showed release of high levels of IL-1β in response to stimulation with LPS, supporting gain of function mechanism of the c.2759G>A (p.Arg920Gln) variant (PMID: 28847925, 29342053). This variant is absent from the gnomAD population database and thus is presumed to be rare. In silico analyses do not support a deleterious effect of the c.2759G>A (p.Arg920Gln) variant on protein function. Based on the available evidence, the c.2759G>A (p.Arg920Gln) variant is classified as Likely Pathogenic.

Comment:

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces arginine with glutamine at codon 920 of the NLRP3 protein (p.Arg920Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate¬†in families¬†with cryopyrin-associated periodic syndromes (CAPS) and¬†autosomal dominant deafness-34 (DFNA34) (PMID:¬†28847925). This variant is also known as p.Arg918Gln in the literature. ClinVar contains an entry for this variant (Variation ID:¬†446409). 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy.	Nakanishi H	Proceedings of the National Academy of Sciences of the United States of America	2017	PMID: 28847925

Text-mined citations for rs1553293095 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001243133.2(NLRP3):c.2753G>A (p.Arg918Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1553293095 ...