ClinVar Genomic variation as it relates to human health
NM_002163.4(IRF8):c.602C>T (p.Ala201Val)
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.
Uncertain significance(2); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002163.4(IRF8):c.602C>T (p.Ala201Val)
Variation ID: 475393 Accession: VCV000475393.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.1 16: 85918417 (GRCh38) [ NCBI UCSC ] 16: 85952023 (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 Jun 12, 2018 Apr 15, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002163.4:c.602C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002154.1:p.Ala201Val missense NM_001363907.1:c.632C>T NP_001350836.1:p.Ala211Val missense NM_001363908.1:c.-11C>T 5 prime UTR NC_000016.10:g.85918417C>T NC_000016.9:g.85952023C>T NG_029333.1:g.24250C>T LRG_294:g.24250C>T LRG_294t1:c.602C>T - Protein change
- A201V, A211V
- Other names
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- Canonical SPDI
- NC_000016.10:85918416: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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0.00300 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00297
1000 Genomes Project 0.00300
The Genome Aggregation Database (gnomAD) 0.00301
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00239
Exome Aggregation Consortium (ExAC) 0.00252
The Genome Aggregation Database (gnomAD), exomes 0.00276
Trans-Omics for Precision Medicine (TOPMed) 0.00323
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 | ||
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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
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. |
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IRF8 | - | - |
GRCh38 GRCh37 |
329 | 401 |
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. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 30, 2024 | RCV000557109.16 | |
Likely benign (2) |
criteria provided, single submitter
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May 4, 2023 | RCV000656479.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 5, 2019 | RCV001193620.2 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 1, 2023 | RCV001200602.15 |
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. |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 32B
Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895047.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Mar 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362569.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: IRF8 c.602C>T (p.Ala201Val) results in a non-conservative amino acid change located in the IRF association domain (Mace 2017) of the encoded protein sequence. … (more)
Variant summary: IRF8 c.602C>T (p.Ala201Val) results in a non-conservative amino acid change located in the IRF association domain (Mace 2017) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0026 in 264914 control chromosomes in the gnomAD database, including 2 homozygotes. c.602C>T has been reported in the literature in a compound heterozygous individual (together with c.671C>T (p.Pro224Leu)) affected with Immunodeficiency 32B (Mace 2017). This genotype was not confirmed in the affected sister and other family members who carried either variant in heterozygosity were unaffected; although the observed phenotypes in this family could be consistent with an autosomal recessive inheritance mode, the available data are not sufficient to confirm the role of the variant of interest in association with the disease. The variant was also reported in heterozygous state in two unrelated individuals with pulmonary nontuberculous mycobacterial disease (PNTM) (Mace 2017, Szymanski 2015). These reports therefore do not provide unequivocal conclusion about the association of the variant with Immunodeficiency 32B. One of these studies also reported experimental evidence and demonstrated decreased NK cell number and function, with interrupted NK cell maturation in the compound heterozygous patient, but normal NK cell number and cytotoxic function in the heterozygous carriers (Mace 2017). These data, however, do not allow convincing conclusion about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 32B
Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000655588.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
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Likely benign
(Feb 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371608.18
First in ClinVar: Jul 16, 2020 Last updated: Apr 15, 2024 |
Comment:
IRF8: BS2
Number of individuals with the variant: 3
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Likely benign
(May 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 32B
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812808.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in IRF8 is predicted to replace alanine with valine at codon 201, p.(Ala201Val). There is a moderate (60-100) physicochemical difference between alanine … (more)
This sequence change in IRF8 is predicted to replace alanine with valine at codon 201, p.(Ala201Val). There is a moderate (60-100) physicochemical difference between alanine and valine. The highest population minor allele frequency is in the Latino/Admixed American population with allele frequency of 0.33% (rs144424711, 131/35004 alleles, 1 homozygotes in gnomAD v2.1). Computational evidence is uninformative for the missense substitution (REVEL = 0.306). This variant has been reported in an individual with NK cell deficiency (PMID: 27893462). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1, BP4, PP4 (less)
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Pathogenic
(Jun 08, 2018)
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no assertion criteria provided
Method: literature only
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IMMUNODEFICIENCY 32B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000778448.1
First in ClinVar: Jun 12, 2018 Last updated: Jun 12, 2018 |
Comment on evidence:
In a patient with immunodeficiency-32B (IMD32B; 226990), who was 1 of 3 affected sibs in the family originally reported by Fleisher et al. (1982), Mace … (more)
In a patient with immunodeficiency-32B (IMD32B; 226990), who was 1 of 3 affected sibs in the family originally reported by Fleisher et al. (1982), Mace et al. (2017) identified compound heterozygous missense mutations in exon 7 of the IRF8 gene: a c.602C-T transition (c.602C-T, NM_002163), resulting in an ala201-to-val (A201V) substitution, and a c.671C-T transition, resulting in a pro224-to-leu (P224L; 601565.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The patient's affected sibs were deceased without available DNA, although paraffin tissue from 1 affected sib showed the P224L mutation; additional studies could not be performed due to degradation of the sample. Both mutations were present at a low frequency in the ExAC database (0.002515 for A201V and 4.4 x 10(-5) for P224L with no homozygotes). Both mutations occurred in the IRF association domain. Studies of patient B cells showed normal IRF8 expression and nuclear localization. The patient had decreased numbers of NK cells and significantly decreased NK cell cytotoxic function. Detailed analysis of patient NK cells showed increased CD56-bright cells and decreased CD56-dim cells compared to controls, indicating a defect in terminal differentiation of NK cells. (less)
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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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Biallelic mutations in IRF8 impair human NK cell maturation and function. | Mace EM | The Journal of clinical investigation | 2017 | PMID: 27893462 |
Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease. | Szymanski EP | American journal of respiratory and critical care medicine | 2015 | PMID: 26038974 |
A non-x-linked syndrome with susceptibility to severe Epstein-Barr virus infections. | Fleisher G | The Journal of pediatrics | 1982 | PMID: 6279813 |
Text-mined citations for rs144424711 ...
HelpRecord last updated Apr 20, 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.