VCV000523654.48 - ClinVar

NM_144687.4(NLRP12):c.1054C>T (p.Arg352Cys)

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.

(10)

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(3); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_144687.4(NLRP12):c.1054C>T (p.Arg352Cys)

Variation ID: 523654 Accession: VCV000523654.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.42 19: 53810605 (GRCh38) [ NCBI UCSC ] 19: 54313859 (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	May 21, 2018	Oct 20, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_144687.4:c.1054C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_653288.1:p.Arg352Cys	missense
NM_001277126.2:c.1054C>T	NP_001264055.1:p.Arg352Cys	missense
NM_001277129.1:c.1054C>T	NP_001264058.1:p.Arg352Cys	missense
NC_000019.10:g.53810605G>A
NC_000019.9:g.54313859G>A
NG_008651.2:g.18790C>T
LRG_181:g.18790C>T
LRG_181t1:c.1054C>T	LRG_181p1:p.Arg352Cys
LRG_181t2:c.1054C>T	LRG_181p2:p.Arg352Cys

... more HGVS ... less HGVS

Protein change

R352C

Other names

Canonical SPDI

NC_000019.10:53810604: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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00019

Trans-Omics for Precision Medicine (TOPMed) 0.00020

Exome Aggregation Consortium (ExAC) 0.00035

The Genome Aggregation Database (gnomAD), exomes 0.00038

Links

ClinGen: CA9639530 OMIM: 609648.0004 dbSNP: rs199881207 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.
NLRP12		-	-	GRCh38 GRCh37	1197	1226

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 2	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Mar 25, 2024	RCV000627081.26
Autoinflammatory syndrome	Likely benign (1)	criteria provided, single submitter	Feb 1, 2020	RCV002263840.4
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Apr 1, 2024	RCV001311905.25

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 benign (Feb 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: SCV002542434.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Uncertain significance (Dec 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cold autoinflammatory syndrome 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV002759339.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Clinical Features: Recurrent fever (present) , Elevated circulating C-reactive protein concentration (present) , Neutrophilia (present) , Knee pain (present)
Likely benign (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial cold autoinflammatory syndrome 2 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805612.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005194793.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (Sep 27, 2019)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Familial cold autoinflammatory syndrome 2 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001158137.2 First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021	Comment: The NLRP12 c.1054C>T; p.Arg352Cys variant (rs199881207) is published in the medical literature in 3 unrelated individuals with periodic fever or autoimmune disease without urticaria (Jeru … (more) The NLRP12 c.1054C>T; p.Arg352Cys variant (rs199881207) is published in the medical literature in 3 unrelated individuals with periodic fever or autoimmune disease without urticaria (Jeru 2011, Rusmini 2016). The variant is reported in the ClinVar database (Variation ID: 523654) and in the general population with an allele frequency of 0.04% (102/282638 alleles) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Experiments in cell culture show this variant did not affect the NF-KB inhibitory activity, but did enhance processing of caspase-1 compared to wild type (Jeru 2011); these authors suggested that this variant may act in a gain of function mechanism, in contrast to NLRP12 nonsense variants that appear to have a loss of function. However, given the limited clinical and functional data, the significance of the variant is uncertain at this time. References: Jeru I et al. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum. 2011 May;63(5):1459-64. Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7. (less)
Likely benign (Dec 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cold autoinflammatory syndrome 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000835067.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (Apr 01, 2024)	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: SCV001502271.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Comment: NLRP12: BP4 Number of individuals with the variant: 4
Uncertain significance (-)	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: SCV001965612.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Apr 18, 2023)	no assertion criteria provided Method: literature only	FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000747891.2 First in ClinVar: May 21, 2018 Last updated: Apr 23, 2023	Publications: PubMed (1) PubMed: 21538323 Comment on evidence: In 2 unrelated patients with cold autoinflammatory syndrome-2 (FCAS2; 611762), Jeru et al. (2011) identified a heterozygous c.1054C-T transition in exon 3 of the NLRP12 … (more) In 2 unrelated patients with cold autoinflammatory syndrome-2 (FCAS2; 611762), Jeru et al. (2011) identified a heterozygous c.1054C-T transition in exon 3 of the NLRP12 gene, resulting in an arg352-to-cys (R352C) substitution in the NBS domain. The mutation, which was found by direct sequencing of the NLRP12 gene, occurred at a CpG dinucleotide and thus could correspond to a hot spot. The patients were of Armenian and Italian descent, respectively, and the mutation was not found in over 200 ethnically matched controls. In vitro functional expression studies in HEK293 cells showed that the mutant protein did not affect the NF-kappa-B (see 164011) inhibitory activity of NLRP12. However, the R352C mutant showed enhanced ability to induce the processing of caspase-1 (CASP1; 147678) compared to wildtype, consistent with a gain-of-function effect. Transfected cells also showed significantly more speck formation compared to controls. Specks represent intracellular aggregates reflecting activation of the caspase-1/IL1B pathway. Although IL1B levels were not ascertained in these patients, the findings suggested that the R352C mutant protein leads to increased CASP1 processing, which would result in increased IL1B secretion and a hyperinflammatory state. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740400.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021

Comment:

The NLRP12 c.1054C>T; p.Arg352Cys variant (rs199881207) is published in the medical literature in 3 unrelated individuals with periodic fever or autoimmune disease without urticaria (Jeru 2011, Rusmini 2016). The variant is reported in the ClinVar database (Variation ID: 523654) and in the general population with an allele frequency of 0.04% (102/282638 alleles) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Experiments in cell culture show this variant did not affect the NF-KB inhibitory activity, but did enhance processing of caspase-1 compared to wild type (Jeru 2011); these authors suggested that this variant may act in a gain of function mechanism, in contrast to NLRP12 nonsense variants that appear to have a loss of function. However, given the limited clinical and functional data, the significance of the variant is uncertain at this time. References: Jeru I et al. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum. 2011 May;63(5):1459-64. Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7.

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
Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes.	Jéru I	Arthritis and rheumatism	2011	PMID: 21538323

Text-mined citations for rs199881207 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_144687.4(NLRP12):c.1054C>T (p.Arg352Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199881207 ...