ClinVar Genomic variation as it relates to human health
NM_001060.6(TBXA2R):c.179G>T (p.Arg60Leu)
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_001060.6(TBXA2R):c.179G>T (p.Arg60Leu)
Variation ID: 12712 Accession: VCV000012712.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.3 19: 3600456 (GRCh38) [ NCBI UCSC ] 19: 3600454 (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 Apr 4, 2013 Feb 25, 2023 May 28, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001060.6:c.179G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001051.1:p.Arg60Leu missense NM_201636.3:c.179G>T NP_963998.2:p.Arg60Leu missense NC_000019.10:g.3600456C>A NC_000019.9:g.3600454C>A NG_013363.1:g.11378G>T LRG_578:g.11378G>T P21731:p.Arg60Leu - Protein change
- R60L
- Other names
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- Canonical SPDI
- NC_000019.10:3600455:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein function Variation Ontology [VariO:0003]
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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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
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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TBXA2R | - | - |
GRCh38 GRCh37 |
145 | 171 |
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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Benign (2) |
criteria provided, single submitter
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May 28, 2019 | RCV000013549.3 | |
Likely risk allele (1) |
no assertion criteria provided
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Nov 4, 2022 | RCV003128127.1 |
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
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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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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Bleeding disorder, platelet-type, 13, susceptibility to
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140953.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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risk factor
(Feb 15, 1996)
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no assertion criteria provided
Method: literature only
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BLEEDING DISORDER, PLATELET-TYPE, 13, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033796.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of 2 unrelated families with autosomal dominant platelet-type bleeding disorder-13 (BDPLT13; 614009) characterized by defective platelet response to TBXA2, Hirata et al. … (more)
In affected members of 2 unrelated families with autosomal dominant platelet-type bleeding disorder-13 (BDPLT13; 614009) characterized by defective platelet response to TBXA2, Hirata et al. (1994) identified a heterozygous 179G-T transversion in the TBXA2R gene, resulting in an arg60-to-leu (R60L) substitution in the first cytoplasmic loop. The proband in 1 family was homozygous for the mutation and had a slightly more severe phenotype. The families had been reported by Ushikubi et al. (1987) and Fuse et al. (1993), respectively, who demonstrated impaired platelet aggregation responses to TBXA2 and its analogs, despite a normal response to thrombin. Expression of the mutant receptor in Chinese hamster ovary cells by Hirata et al. (1994) showed decreased agonist-induced second messenger formation despite normal ligand binding affinities. Dominant inheritance of the disorder suggested that the mutation produces a dominant-negative effect. Hirata et al. (1996) showed that the R60L mutant of the TXR-alpha isoform of the human TXA2 receptor, which had been shown to impair phospholipase C activation, also impaired adenylyl cyclase stimulation, whereas TXR-beta with the same mutation retained its activity to inhibit adenylyl cyclase. (less)
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Likely risk allele
(Nov 04, 2022)
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no assertion criteria provided
Method: case-control
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Asthma
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Allergology and Ecology Laboratory, University of Burdwan
Accession: SCV003761534.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
Comment:
STRING analysis showed that TBXA2R are involved in interaction with different known and predicted Gq proteins (guanine nucleotide-binding G protein, subunits alpha, group q). Out … (more)
STRING analysis showed that TBXA2R are involved in interaction with different known and predicted Gq proteins (guanine nucleotide-binding G protein, subunits alpha, group q). Out of all Gq proteins, GNA11 acts as an activator of phospholipase C (PLC). PLC hydrolyses phosphoinositides into the two stimulatory second messengers - inositol 1,4,5-triphosphate (IP3) and diacylglycerol. IP3 enhances cytoplasmic free calcium level and diacylglycerol (DAG) activates protein kinase C (PKC). Activated protein kinase C either directly phosphorylates LTC4 synthase enzyme and inactivates it or this regulation may involve another regulatory protein which is yet to be discovered. Inactivation of LTC4 synthase leads to reduction of Leukotriene C4 (LTC4) biosynthesis in platelets. However, in the case of risk allele rs34377097 T-bearing individuals, the non-synonymous polymorphism (R60L) in TBXA2R protein inhibits the interaction between GNA11 and TBXA2R due to the change in the positive charge potentiality at the cytoplasmic domain. This is in line with Hirata et al. 1996, who demonstrated that the R60L polymorphism significantly reduces PLC activity. That leads to simultaneous inactivation of PKC which ultimately results in LTC4 synthase enzyme activation. Activation of this enzyme leads to LTA4 to LTC4 conversion which results in acute asthmatic response including broncho-constriction, tracheolar constriction and increased mucus secretion. (less)
Number of individuals with the variant: 250
Age: 5-70 years
Sex: mixed
Ethnicity/Population group: Bengali
Geographic origin: West Bengal, India
Comment on evidence:
The frequency of the rs34377097 TT genotype was significantly higher in asthma patients than in controls (OR=5.81, P=0.03).
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein function
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Allergology and Ecology Laboratory, University of Burdwan
Accession: SCV003761534.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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In silico analysis of single nucleotide polymorphism (rs34377097) of TBXA2R gene and pollen induced bronchial asthma susceptibility in West Bengal population, India. | Ganai I | Frontiers in immunology | 2023 | DOI: 10.3389/fimmu.2023.1089514 |
Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation. | Hirata T | The Journal of clinical investigation | 1996 | PMID: 8613548 |
Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder. | Hirata T | The Journal of clinical investigation | 1994 | PMID: 7929844 |
Defective signal transduction induced by thromboxane A2 in a patient with a mild bleeding disorder: impaired phospholipase C activation despite normal phospholipase A2 activation. | Fuse I | Blood | 1993 | PMID: 8428006 |
Hemorrhagic thrombocytopathy with platelet thromboxane A2 receptor abnormality: defective signal transduction with normal binding activity. | Ushikubi F | Thrombosis and haemostasis | 1987 | PMID: 2955539 |
Text-mined citations for rs34377097 ...
HelpRecord last updated Jan 26, 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.