ClinVar Genomic variation as it relates to human health
NM_005535.3(IL12RB1):c.517C>T (p.Arg173Trp)
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_005535.3(IL12RB1):c.517C>T (p.Arg173Trp)
Variation ID: 1339542 Accession: VCV001339542.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.11 19: 18077548 (GRCh38) [ NCBI UCSC ] 19: 18188358 (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 Feb 11, 2022 Feb 14, 2024 Dec 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005535.3:c.517C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005526.1:p.Arg173Trp missense NM_001290023.2:c.517C>T NP_001276952.1:p.Arg173Trp missense NM_001290024.1:c.637C>T NP_001276953.1:p.Arg213Trp missense NM_153701.3:c.517C>T NP_714912.1:p.Arg173Trp missense NC_000019.10:g.18077548G>A NC_000019.9:g.18188358G>A NG_007366.2:g.26402C>T LRG_72:g.26402C>T - Protein change
- R173W, R213W
- Other names
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- Canonical SPDI
- NC_000019.10:18077547:G:A
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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.
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The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- Links
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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IL12RB1 | - | - |
GRCh38 GRCh37 |
516 | 534 |
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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2023 | RCV001824251.7 |
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
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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
(Dec 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
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Genomics Facility, Ludwig-Maximilians-Universität München
Accession: SCV002073890.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Clinical Features:
Recurrent mycobacterial infections (present)
Age: 0-9 years
Sex: male
Tissue: PBMCs
Method: Agilent V6+UTR exome enrichment, Illumina NextSeq 500 sequencing
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573246.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). While this variant results in missense change, … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.55). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001339542). The homozygous variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21057261, 30715640, 31158284). A different missense change at the same codon (p.Arg173Pro) has been reported to be associated with IL12RB1-related disorder (ClinVar ID: VCV000827714/ PMID: 11368122). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Vasculitis (present) , Cutaneous abscess (present) , Infective arthritis (present) , Pneumonia (present) , Lymphadenitis (present)
Zygosity: Homozygote
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Pathogenic
(Dec 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002244757.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the IL12RB1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the IL12RB1 protein (p.Arg173Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Mendelian susceptibility to mycobacterial disease (PMID: 21057261, 30715640, 31158284). ClinVar contains an entry for this variant (Variation ID: 1339542). 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) performed at Invitae indicates that this missense variant is expected to disrupt IL12RB1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (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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Characterization of two novel mutations in IL-12R signaling in MSMD patients. | Fayez EA | Pathogens and disease | 2019 | PMID: 31158284 |
Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease. | Sarrafzadeh SA | Journal of clinical immunology | 2019 | PMID: 30715640 |
Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries. | de Beaucoudrey L | Medicine | 2010 | PMID: 21057261 |
Mycobacterium fortuitum-chelonae complex infection in a child with complete interleukin-12 receptor beta 1 deficiency. | Aksu G | The Pediatric infectious disease journal | 2001 | PMID: 11368122 |
Text-mined citations for rs144702323 ...
HelpRecord last updated Sep 29, 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.