VCV000004370.29 - ClinVar

NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val)

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.

(11)

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.

Pathogenic/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.1316C>T (p.Ala439Val)

Variation ID: 4370 Accession: VCV000004370.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q44 1: 247424765 (GRCh38) [ NCBI UCSC ] 1: 247588067 (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	Mar 6, 2014	Nov 24, 2024	Sep 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001243133.2:c.1316C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230062.1:p.Ala439Val	missense
NM_001079821.3:c.1316C>T	NP_001073289.2:p.Ala439Val	missense
NM_001127461.3:c.1316C>T	NP_001120933.2:p.Ala439Val	missense
NM_001127462.3:c.1316C>T	NP_001120934.2:p.Ala439Val	missense
NM_004895.5:c.1322C>T	NP_004886.3:p.Ala441Val	missense
NM_183395.3:c.1316C>T	NP_899632.2:p.Ala439Val	missense
NC_000001.11:g.247424765C>T
NC_000001.10:g.247588067C>T
NG_007509.2:g.13593C>T
LRG_197:g.13593C>T
LRG_197t1:c.1322C>T	LRG_197p1:p.Ala441Val

... more HGVS ... less HGVS

Protein change

A439V, A441V

Other names

Canonical SPDI

NC_000001.11:247424764:C:T

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: CA280958 OMIM: 606416.0001 dbSNP: rs121908146 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	985	1068

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.
Familial cold autoinflammatory syndrome 1	Likely pathogenic (3)	criteria provided, single submitter	Jul 26, 2023	RCV000004618.17
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 1, 2023	RCV000214900.24
Cryopyrin associated periodic syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 20, 2023	RCV000701554.16
Chronic infantile neurological, cutaneous and articular syndrome Familial amyloid nephropathy with urticaria AND deafness Familial cold autoinflammatory syndrome 1 Hearing loss, autosomal dominant 34, with or without inflammation Keratitis fugax hereditaria	Pathogenic (1)	criteria provided, single submitter	Jul 29, 2021	RCV002476928.8
Autoinflammatory syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 6, 2021	RCV002262553.10

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.
Pathogenic (Jul 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cold autoinflammatory syndrome 1 Keratitis fugax hereditaria Familial amyloid nephropathy with urticaria AND deafness Chronic infantile neurological, cutaneous and articular syndrome Hearing loss, autosomal dominant 34, with or without inflammation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002784124.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely pathogenic (Jul 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cold autoinflammatory syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761654.2 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2023	Publications: PubMed (2) PubMed: 11687797‚ 27134254 Comment: The NLRP3 c.1316C>T variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PP1_Strong) The NLRP3 c.1316C>T variant (also known as p.Ala441Val) is a single nucleotide change … (more) The NLRP3 c.1316C>T variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PP1_Strong) The NLRP3 c.1316C>T variant (also known as p.Ala441Val) is a single nucleotide change in exon 3/9 of the NLRP3 gene, which is predicted to change the amino acid alanine at position 439 in the protein to valine. The variant has been reported in probands with a clinical presentation of Familial Cold Autoinflammatory Syndrome (PS4_Moderate). This variant is absent from population databases (PM2). Segregation with disease is noted within 2 large families, with 19 mutation positive individuals. (PP1_strong) (PubMed: 11687797, 27134254). The variant has been reported in dbSNP (rs121908146) and in the HGMD database: CM013248. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 4370). (less)
Pathogenic (Jun 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000278944.6 First in ClinVar: May 29, 2016 Last updated: Dec 19, 2017	Comment: Published functional studies demonstrate that individuals with A441V have increased secretion of inflammatory cytokines, which correlates with disease severity (Rieber et al., 2015); Not observed … (more) Published functional studies demonstrate that individuals with A441V have increased secretion of inflammatory cytokines, which correlates with disease severity (Rieber et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26115477, 22377911, 25596455, 26245507, 11687797, 26931528, 27134254, 28956000, 15801036, 31057541, 30568124, 31777803, 27535533, 19302049) (less)
Pathogenic (Jan 06, 2021)	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: SCV002542594.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Pathogenic (Nov 23, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885859.5 First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023	Comment: The NLRP3 c.1322C>T; p.Ala441Val variant (rs121908146), also known as Ala439Val, is published in the medical literature in several individuals and families with various autoinflammatory syndromes … (more) The NLRP3 c.1322C>T; p.Ala441Val variant (rs121908146), also known as Ala439Val, is published in the medical literature in several individuals and families with various autoinflammatory syndromes (Aoyama 2012, Hentgen 2005, Hoffman 2001, Houx 2015, Parker 2016) and is described as one of the more common pathogenic variants (Cuisset 2010). The variant is described as occurring de novo in at least one family (Hoffman 2001) and also has been shown to segregate with disease (Hoffman 2001, Hentgen 2005). The variant is reported in ClinVar (Variation ID: 4370), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 441 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.481). Considering available information, this variant is classified as pathogenic. References: Aoyama K et al. Cryopyrin-associated periodic syndrome: a case report and review of the Japanese literature. Acta Derm Venereol. 2012 Jul;92(4):395-8. PMID: 22377911. Cuisset L et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011 Mar;70(3):495-9. PMID: 21109514. Hentgen V et al. Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome. J Rheumatol. 2005 Apr;32(4):747-51. PMID: 15801036. PMID: 11687797. Hoffman HM et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301-5. PMID: 11687797. Houx L et al. Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study. Arthritis Rheumatol. 2015 Nov;67(11):3027-36. PMID: 26245507. Parker T et al. Neurology of the cryopyrin-associated periodic fever syndrome. Eur J Neurol. 2016 Jul;23(7):1145-51. PMID: 26931528. (less)
Pathogenic (Sep 20, 2023)	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: SCV000830359.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28492532‚ 11687797‚ 15801036‚ 25596455‚ 26245507‚ 26931528‚ 27134254 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NLRP3 protein function. ClinVar contains an entry for this variant (Variation ID: 4370). This variant is also known as A439V or C1316T. This missense change has been observed in individuals with NLRP3-related disease (PMID: 11687797, 15801036, 25596455, 26245507, 26931528, 27134254). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 441 of the NLRP3 protein (p.Ala441Val). (less)
Pathogenic (Aug 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414316.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (11) PubMed: 11687797‚ 15801036‚ 22377911‚ 25596455‚ 26245507‚ 26931528‚ 27134254‚ 30568124‚ 31057541‚ 31777803‚ 34099780 Comment: PP1_very_strong, PP4, PM2, PM6, PS3_moderate, PS4 Number of individuals with the variant: 1
Pathogenic (Nov 01, 2001)	no assertion criteria provided Method: literature only	FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024792.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016	Publications: PubMed (2) PubMed: 5173311‚ 11687797 Comment on evidence: In a 4-generation family with familial cold autoinflammatory syndrome (FCAS1; 120100) previously reported by Shepard (1971), Hoffman et al. (2001) identified a C-to-T transition at … (more) In a 4-generation family with familial cold autoinflammatory syndrome (FCAS1; 120100) previously reported by Shepard (1971), Hoffman et al. (2001) identified a C-to-T transition at nucleotide 1316 in exon 3 of the CIAS1 gene, resulting in an alanine-to-valine substitution at codon 439 (A439V). (less)
Pathogenic (-)	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: SCV001931798.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958584.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: not provided	Familial cold urticaria Affected status: not provided Allele origin: unknown	Unité médicale des maladies autoinflammatoires, CHRU Montpellier Accession: SCV000116318.1 First in ClinVar: Mar 06, 2014 Last updated: Mar 06, 2014 Comment: also involved in OMIM 191900 and 607115
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Comment:

The NLRP3 c.1316C>T variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PP1_Strong) The NLRP3 c.1316C>T variant (also known as p.Ala441Val) is a single nucleotide change in exon 3/9 of the NLRP3 gene, which is predicted to change the amino acid alanine at position 439 in the protein to valine. The variant has been reported in probands with a clinical presentation of Familial Cold Autoinflammatory Syndrome (PS4_Moderate). This variant is absent from population databases (PM2). Segregation with disease is noted within 2 large families, with 19 mutation positive individuals. (PP1_strong) (PubMed: 11687797, 27134254). The variant has been reported in dbSNP (rs121908146) and in the HGMD database: CM013248. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 4370).

Comment:

Published functional studies demonstrate that individuals with A441V have increased secretion of inflammatory cytokines, which correlates with disease severity (Rieber et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26115477, 22377911, 25596455, 26245507, 11687797, 26931528, 27134254, 28956000, 15801036, 31057541, 30568124, 31777803, 27535533, 19302049)

Comment:

The NLRP3 c.1322C>T; p.Ala441Val variant (rs121908146), also known as Ala439Val, is published in the medical literature in several individuals and families with various autoinflammatory syndromes (Aoyama 2012, Hentgen 2005, Hoffman 2001, Houx 2015, Parker 2016) and is described as one of the more common pathogenic variants (Cuisset 2010). The variant is described as occurring de novo in at least one family (Hoffman 2001) and also has been shown to segregate with disease (Hoffman 2001, Hentgen 2005). The variant is reported in ClinVar (Variation ID: 4370), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 441 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.481). Considering available information, this variant is classified as pathogenic. References: Aoyama K et al. Cryopyrin-associated periodic syndrome: a case report and review of the Japanese literature. Acta Derm Venereol. 2012 Jul;92(4):395-8. PMID: 22377911. Cuisset L et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011 Mar;70(3):495-9. PMID: 21109514. Hentgen V et al. Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome. J Rheumatol. 2005 Apr;32(4):747-51. PMID: 15801036. PMID: 11687797. Hoffman HM et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301-5. PMID: 11687797. Houx L et al. Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study. Arthritis Rheumatol. 2015 Nov;67(11):3027-36. PMID: 26245507. Parker T et al. Neurology of the cryopyrin-associated periodic fever syndrome. Eur J Neurol. 2016 Jul;23(7):1145-51. PMID: 26931528.

Comment:

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NLRP3 protein function. ClinVar contains an entry for this variant (Variation ID: 4370). This variant is also known as A439V or C1316T. This missense change has been observed in individuals with NLRP3-related disease (PMID: 11687797, 15801036, 25596455, 26245507, 26931528, 27134254). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 441 of the NLRP3 protein (p.Ala441Val).

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
Ocular manifestations in Chinese adult patients with NLRP3-associated autoinflammatory disease.	Meng T	Scientific reports	2021	PMID: 34099780
The NLRP3 p.A441V Mutation in NLRP3-AID Pathogenesis: Functional Consequences, Phenotype-Genotype Correlations and Evidence for a Recurrent Mutational Event.	Awad F	ACR open rheumatology	2019	PMID: 31777803
Muckle-Wells Syndrome Across Four Generations in One Czech Family: Natural Course of the Disease.	Fingerhutová Š	Frontiers in immunology	2019	PMID: 31057541
A Rare Case of Cryopyrin-associated Periodic Syndrome in an Elderly Woman with NLRP3 and MEFV Mutations.	Nakamichi S	Internal medicine (Tokyo, Japan)	2019	PMID: 30568124
NLRP3 A439V Mutation in a Large Family with Cryopyrin-associated Periodic Syndrome: Description of Ophthalmologic Symptoms in Correlation with Other Organ Symptoms.	Sobolewska B	The Journal of rheumatology	2016	PMID: 27134254
Neurology of the cryopyrin-associated periodic fever syndrome.	Parker T	European journal of neurology	2016	PMID: 26931528
Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study.	Houx L	Arthritis & rheumatology (Hoboken, N.J.)	2015	PMID: 26245507
A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants.	Rieber N	Clinical immunology (Orlando, Fla.)	2015	PMID: 25596455
Cryopyrin-associated periodic syndrome: a case report and review of the Japanese literature.	Aoyama K	Acta dermato-venereologica	2012	PMID: 22377911
Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome.	Hentgen V	The Journal of rheumatology	2005	PMID: 15801036
Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome.	Hoffman HM	Nature genetics	2001	PMID: 11687797
Cold hypersensitivity.	Shepard MK	Birth defects original article series	1971	PMID: 5173311
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Text-mined citations for rs121908146 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908146 ...