NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val) AND Familial cold autoinflammatory syndrome 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Jul 26, 2023
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:: RCV000004618.17

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val)]

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

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.1316C>T (p.Ala439Val)

HGVS:

NC_000001.11:g.247424765C>T
NG_007509.2:g.13593C>T
NM_001079821.3:c.1316C>T
NM_001127461.3:c.1316C>T
NM_001127462.3:c.1316C>T
NM_001243133.2:c.1316C>TMANE SELECT
NM_004895.5:c.1322C>T
NM_183395.3:c.1316C>T
NP_001073289.2:p.Ala439Val
NP_001120933.2:p.Ala439Val
NP_001120934.2:p.Ala439Val
NP_001230062.1:p.Ala439Val
NP_001230062.1:p.Ala439Val
NP_004886.3:p.Ala441Val
NP_004886.3:p.Ala441Val
NP_899632.2:p.Ala439Val
LRG_197t1:c.1322C>T
LRG_197:g.13593C>T
LRG_197p1:p.Ala441Val
NC_000001.10:g.247588067C>T
NM_001243133.1:c.1316C>T
NM_004895.4:c.1322C>T

Protein change:

A439V; ALA439VAL

Links:

OMIM: 606416.0001; dbSNP: rs121908146

NCBI 1000 Genomes Browser:

rs121908146

Molecular consequence:

NM_001079821.3:c.1316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127461.3:c.1316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127462.3:c.1316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243133.2:c.1316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004895.5:c.1322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_183395.3:c.1316C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cold autoinflammatory syndrome 1 (FCAS1)
Synonyms:: CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME 1; Familial cold inflammatory syndrome 1
Identifiers:: MONDO: MONDO:0007349; MedGen: C4551895; Orphanet: 47045; OMIM: 120100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024792	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2001)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 5173311, 11687797
SCV000116318	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	no classification provided	not provided	unknown	not provided
SCV002761654	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11687797, 27134254, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024792

OMIM

no assertion criteria provided

Pathogenic
(Nov 1, 2001)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000116318

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

no classification provided

not provided

unknown

not provided

SCV002761654

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 26, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cold hypersensitivity.

Shepard MK.

Birth Defects Orig Artic Ser. 1971 Jun;7(8):352. No abstract available.

PubMed [citation]

PMID:: 5173311

Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome.

Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD.

Nat Genet. 2001 Nov;29(3):301-5.

PubMed [citation]

PMID:: 11687797
PMCID:: PMC4322000

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000024792.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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).

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

From Unité médicale des maladies autoinflammatoires, CHRU Montpellier, SCV000116318.1

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

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

From Genetics and Molecular Pathology, SA Pathology, SCV002761654.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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).

#	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: Nov 3, 2024

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