ClinVar Genomic variation as it relates to human health
NM_016123.4(IRAK4):c.877C>T (p.Gln293Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_016123.4(IRAK4):c.877C>T (p.Gln293Ter)
Variation ID: 3839 Accession: VCV000003839.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q12 12: 43778238 (GRCh38) [ NCBI UCSC ] 12: 44172041 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 8, 2014 Oct 8, 2024 May 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016123.4:c.877C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057207.2:p.Gln293Ter nonsense NM_001114182.3:c.877C>T NP_001107654.1:p.Gln293Ter nonsense NM_001145256.2:c.505C>T NP_001138728.1:p.Gln169Ter nonsense NM_001145257.2:c.505C>T NP_001138729.1:p.Gln169Ter nonsense NM_001145258.2:c.505C>T NP_001138730.1:p.Gln169Ter nonsense NM_001351338.2:c.505C>T NP_001338267.1:p.Gln169Ter nonsense NM_001351339.2:c.505C>T NP_001338268.1:p.Gln169Ter nonsense NM_001351340.2:c.505C>T NP_001338269.1:p.Gln169Ter nonsense NM_001351341.2:c.505C>T NP_001338270.1:p.Gln169Ter nonsense NM_001351342.2:c.505C>T NP_001338271.1:p.Gln169Ter nonsense NM_001351343.2:c.268C>T NP_001338272.1:p.Gln90Ter nonsense NM_001351344.2:c.268C>T NP_001338273.1:p.Gln90Ter nonsense NM_001351345.2:c.877C>T NP_001338274.1:p.Gln293Ter nonsense NC_000012.12:g.43778238C>T NC_000012.11:g.44172041C>T NG_009892.1:g.24295C>T LRG_75:g.24295C>T LRG_75t1:c.877C>T LRG_75p1:p.Gln293Ter - Protein change
- Q293*, Q169*, Q90*
- Other names
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- Canonical SPDI
- NC_000012.12:43778237:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00018
The Genome Aggregation Database (gnomAD), exomes 0.00023
Trans-Omics for Precision Medicine (TOPMed) 0.00026
The Genome Aggregation Database (gnomAD) 0.00035
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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IRAK4 | - | - |
GRCh38 GRCh37 |
316 | 337 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV000004043.24 | |
IRAK4-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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May 1, 2023 | RCV003390639.4 |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 1, 2024 | RCV001556912.18 |
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
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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
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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. |
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Pathogenic
(Nov 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 67
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915596.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The IRAK4 c.877C>T (p.Gln293Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of … (more)
The IRAK4 c.877C>T (p.Gln293Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Gln293Ter variant has been identified in a total of 23 individuals with IRAK4 deficiency including 15 homozygotes and eight compound heterozygotes (Picard et al.2003; Picard et al. 2010; Andres et al. 2013; Frans et al. 2015). The p.Gln293Ter variant was absent from 160 healthy controls and is reported at a frequency of 0.000482 in the European (non-Finnish) population of the Genome Aggregation Database. Ku et al. (2007) used EBV-transformed B lymphocyte cell lines (B-EBVs) and SV40-transformed fibroblast cell lines (SV40-fibroblast) from a healthy control and IRAK4-deficient patients to demonstrate that cell lines bearing the p.Gln293Ter variant had low levels of detectable full length IRAK4 mRNA and no IRAK4 protein. In addition, B-EBVs bearing the p.Gln293Ter variant did not respond to TLR7 and TLR8 agonists as measured by TNF-alpha production, while SV40-fibroblasts bearing the p.Gln293Ter variant did not respond to IL1-beta as assessed by measuring IL6 production, together suggesting a complete IRAK4 deficiency and absence of IRAK4-dependent TIR signalling. Based on the collective evidence and the potential impact of stop-gained variants, the p.Gln293Ter variant is classified as pathogenic for IRAK4 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Aug 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 67
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440146.2
First in ClinVar: Oct 30, 2020 Last updated: Sep 25, 2021 |
Comment:
This variant was identified as compound heterozygous with NM_016123.3:c.1148G>T.
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Pathogenic
(May 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001778578.2
First in ClinVar: Aug 12, 2021 Last updated: Jun 03, 2023 |
Comment:
Published functional studies demonstrate a damaging effect of the Q293X with undetectable mRNA levels in cells lines harboring this variant (Picard et al., 2003; Yamamot … (more)
Published functional studies demonstrate a damaging effect of the Q293X with undetectable mRNA levels in cells lines harboring this variant (Picard et al., 2003; Yamamot et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29431110, 17544092, 17114497, 24316379, 25344726, 25525159, 26472314, 29707745, 12637671, 21057262, 17893200, 29531937, 31526803, 31980526, 31589614, 32888943, 31345219, 33083971) (less)
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Pathogenic
(May 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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IRAK4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119883.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The IRAK4 c.877C>T variant is predicted to result in premature protein termination (p.Gln293*). This variant has been reported to be causative for autosomal recessive IRAK4 … (more)
The IRAK4 c.877C>T variant is predicted to result in premature protein termination (p.Gln293*). This variant has been reported to be causative for autosomal recessive IRAK4 deficiency (see for example - Picard et al. 2003. PubMed ID: 12637671; Picard et al. 2010. PubMed ID: 21057262; Lavine et al. 2007. PubMed ID: 17544092). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-44172041-C-T). Nonsense variants in IRAK4 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 67
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000762275.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln293*) in the IRAK4 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln293*) in the IRAK4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IRAK4 are known to be pathogenic (PMID: 17893200, 21057262). This variant is present in population databases (rs121908002, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with IRAK4 deficiency (PMID: 12637671, 12925671, 19663824, 20621347, 25344726, 26472314). ClinVar contains an entry for this variant (Variation ID: 3839). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821701.13
First in ClinVar: Jan 21, 2023 Last updated: Oct 08, 2024 |
Comment:
IRAK4: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Number of individuals with the variant: 3
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Pathogenic
(Apr 28, 2022)
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criteria provided, single submitter
Method: research
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Immunodeficiency 67
Affected status: yes
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV002515830.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG codes: PVS1, PS3, PM2, PM3_VeryStrong, PP1_VeryStrong
Number of individuals with the variant: 1
Clinical Features:
Hypotonia (present) , Ascites (present) , Retinopathy of prematurity (present)
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Pathogenic
(Dec 01, 2006)
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no assertion criteria provided
Method: literature only
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IMMUNODEFICIENCY 67
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024209.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 28, 2020 |
Comment on evidence:
In 2 unrelated individuals with immunodeficiency-67 (IMD67; 607676), one of whom was originally reported by Haraguchi et al. (1998), Picard et al. (2003) identified a … (more)
In 2 unrelated individuals with immunodeficiency-67 (IMD67; 607676), one of whom was originally reported by Haraguchi et al. (1998), Picard et al. (2003) identified a homozygous c.877C-T transition in exon 8 of the IRAK4 gene, resulting in a gln293-to-ter (Q293X) substitution. The parents of 1 patient were unavailable for study; the mother of the second patient was heterozygous for the mutation and the child inherited 2 maternal copies owing to segmental uniparental isodisomy. The mutation was not found in 60 healthy individuals. No IRAK4 mRNA or protein was identified in patient cells, consistent with a complete loss of function. Medvedev et al. (2003) reported a patient with IMD67 who was compound heterozygous for 2 mutations in the IRAK4 gene: Q293X and a 2-bp deletion (c.620delAC) (606883.0003), resulting in a frameshift and premature termination. Both mutations resulted in proteins with intact death domains but truncated kinase domains, precluding expression of full-length IRAK4 and conferring a recessive phenotype. Davidson et al. (2006) identified homozygosity for the Q293X mutation in a patient with recurrent Streptococcus pneumonia bacteremia and in the patient's deceased older brother. The patient's parents and 2 healthy brothers were heterozygous for the mutation, which was not present in controls. Characterization of the patient's IRAK4-deficient primary dermal fibroblasts and peripheral blood mononuclear cells revealed cell type-specific and ligand-specific defects in cytokine responses. In 2 sibs, born of unrelated parents of English descent, with IMD67, Lavine et al. (2007) identified a homozygous Q293X mutation in the IRAK4 gene. Patient blood cells showed impaired IL6 production in response to LPS and IL1B. There was also some evidence of T-cell dysfunction. The sibs, who were twins, had severe and recurrent invasive infections in childhood. However, they were treated successfully with IVIg, and had no further significant infections after stopping the medication around 18 years of age. They had a similarly affected sib who died in infancy from Staphylococcus aureus meningitis; DNA from that patient was not studied. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929423.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001960122.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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PID in Disguise: Molecular Diagnosis of IRAK-4 Deficiency in an Adult Previously Misdiagnosed With Autosomal Dominant Hyper IgE Syndrome. | Frans G | Journal of clinical immunology | 2015 | PMID: 26472314 |
A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4. | Alsina L | Nature immunology | 2014 | PMID: 25344726 |
Even in pneumococcal sepsis CD62L shedding on granulocytes proves to be a reliable functional test for the diagnosis of interleukin-1 receptor-associated kinase-4 deficiency. | Andres O | The Pediatric infectious disease journal | 2013 | PMID: 23538514 |
Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. | Picard C | Medicine | 2010 | PMID: 21057262 |
Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients. | McDonald DR | The Journal of allergy and clinical immunology | 2010 | PMID: 20621347 |
Impaired neutrophil migration and phagocytosis in IRAK-4 deficiency. | Bouma G | British journal of haematology | 2009 | PMID: 19663824 |
Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. | Ku CL | The Journal of experimental medicine | 2007 | PMID: 17893200 |
Cellular and humoral aberrations in a kindred with IL-1 receptor-associated kinase 4 deficiency. | Lavine E | The Journal of allergy and clinical immunology | 2007 | PMID: 17544092 |
IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells. | Davidson DJ | Journal of immunology (Baltimore, Md. : 1950) | 2006 | PMID: 17114497 |
Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. | Medvedev AE | The Journal of experimental medicine | 2003 | PMID: 12925671 |
Pyogenic bacterial infections in humans with IRAK-4 deficiency. | Picard C | Science (New York, N.Y.) | 2003 | PMID: 12637671 |
Interleukin 12 deficiency associated with recurrent infections. | Haraguchi S | Proceedings of the National Academy of Sciences of the United States of America | 1998 | PMID: 9789052 |
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Text-mined citations for rs121908002 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.