VCV000234290.58 - ClinVar

NM_001243133.2(NLRP3):c.2176A>G (p.Ser726Gly)

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.

(14)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(1); Likely benign(8)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001243133.2(NLRP3):c.2176A>G (p.Ser726Gly)

Variation ID: 234290 Accession: VCV000234290.58

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q44 1: 247429610 (GRCh38) [ NCBI UCSC ] 1: 247592912 (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 6, 2016	Oct 20, 2024	Feb 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001243133.2:c.2176A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230062.1:p.Ser726Gly	missense
NM_001079821.3:c.2176A>G	NP_001073289.2:p.Ser726Gly	missense
NM_001127461.3:c.2176A>G	NP_001120933.2:p.Ser726Gly	missense
NM_001127462.3:c.2150+4011A>G		intron variant
NM_004895.5:c.2182A>G	NP_004886.3:p.Ser728Gly	missense
NM_183395.3:c.2150+4011A>G		intron variant
NC_000001.11:g.247429610A>G
NC_000001.10:g.247592912A>G
NG_007509.2:g.18438A>G
LRG_197:g.18438A>G
LRG_197t1:c.2182A>G	LRG_197p1:p.Ser728Gly

... more HGVS ... less HGVS

Protein change

S728G, S726G

Other names

Canonical SPDI

NC_000001.11:247429609:A:G

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.

0.00020 (G)

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

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00049

The Genome Aggregation Database (gnomAD) 0.00049

The Genome Aggregation Database (gnomAD), exomes 0.00052

Trans-Omics for Precision Medicine (TOPMed) 0.00053

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

Links

ClinGen: CA1495151 dbSNP: rs147946775 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	982	1065

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.
not specified	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Feb 6, 2024	RCV000216458.19
Familial amyloid nephropathy with urticaria AND deafness	Likely benign (1)	criteria provided, single submitter	Apr 28, 2017	RCV000303538.5
Chronic infantile neurological, cutaneous and articular syndrome	Likely benign (1)	criteria provided, single submitter	Apr 28, 2017	RCV000263610.5
Familial cold autoinflammatory syndrome 1	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Apr 28, 2017	RCV000626053.8
Cryopyrin associated periodic syndrome	Likely benign (1)	criteria provided, single submitter	Jan 19, 2024	RCV000552226.14
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jul 1, 2023	RCV001172030.26
Autoinflammatory syndrome	Likely benign (1)	criteria provided, single submitter	Jan 1, 2020	RCV002262814.3
NLRP3-related disorder	Likely benign (1)	no assertion criteria provided	Sep 23, 2022	RCV004532811.2

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.
Uncertain significance (May 20, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cold autoinflammatory syndrome 1 Proband is a 32 year old female (more...) (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000746675.1 First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018	Number of individuals with the variant: 4 Clinical Features: Vitamin D deficiency (present) , Urticaria (present) , Tonsillitis (present) , Recurrent pharyngitis (present) , Paresthesia (present) , Myalgia (present) , Episodic fever (present) , … (more) Vitamin D deficiency (present) , Urticaria (present) , Tonsillitis (present) , Recurrent pharyngitis (present) , Paresthesia (present) , Myalgia (present) , Episodic fever (present) , Elevated C-reactive protein level (present) , Angioedema (present) , Abnormality of the eye (present) , Abnormality of complement system (present) , Abnormal sudomotor regulation (present) (less) Family history: yes Age: 11-32 years Sex: female Ethnicity/Population group: White Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2016-05-20 Testing laboratory interpretation: Uncertain significance
Likely benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial cold autoinflammatory syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000356984.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 25821352‚ 25979514 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Chronic infantile neurological, cutaneous and articular syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000356985.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 25821352‚ 25979514 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial amyloid nephropathy with urticaria AND deafness Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000356983.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 25821352‚ 25979514 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 21, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000278947.5 First in ClinVar: May 29, 2016 Last updated: Mar 08, 2017	Comment: This variant is associated with the following publications: (PMID: 25821352)
Likely benign (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cryopyrin associated periodic syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000646267.10 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (Apr 18, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604552.2 First in ClinVar: Mar 08, 2017 Last updated: Feb 20, 2024
Likely benign (Apr 12, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967262.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (1) PubMed: 25821352 Comment: The p.Ser728Gly variant is classified as likely benign because it has been ident ified in 0.08% (105/126674) of European chromosomes by the Genome Aggregation Da … (more) The p.Ser728Gly variant is classified as likely benign because it has been ident ified in 0.08% (105/126674) of European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147946775). It has bee n reported in one individual with PFAPA, but was also identified in 2 unaffected family members (Perko 2015). ACMG/AMP Criteria applied: BS1. (less) Number of individuals with the variant: 1
Likely benign (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002542616.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Uncertain significance (Feb 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004243538.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Benign (Jul 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001334959.25 First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024	Comment: NLRP3: BP4, BS1, BS2 Number of individuals with the variant: 5
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001978086.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980001.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely benign (Sep 23, 2022)	no assertion criteria provided Method: clinical testing	NLRP3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004733406.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

The p.Ser728Gly variant is classified as likely benign because it has been ident ified in 0.08% (105/126674) of European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147946775). It has bee n reported in one individual with PFAPA, but was also identified in 2 unaffected family members (Perko 2015). ACMG/AMP Criteria applied: BS1.

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
Diagnosis of cryopyrin-associated periodic syndrome: challenges, recommendations and emerging concepts.	Sarrabay G	Expert review of clinical immunology	2015	PMID: 25979514
Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients.	Perko D	Mediators of inflammation	2015	PMID: 25821352

Text-mined citations for rs147946775 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001243133.2(NLRP3):c.2176A>G (p.Ser726Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147946775 ...