ClinVar Miner

Submissions for variant NM_001060.6(TBXA2R):c.179G>T (p.Arg60Leu)

gnomAD frequency: 0.00002  dbSNP: rs34377097
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000013549 SCV001140953 benign Bleeding disorder, platelet-type, 13, susceptibility to 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000013549 SCV000033796 risk factor Bleeding disorder, platelet-type, 13, susceptibility to 1996-02-15 no assertion criteria provided literature only
Allergology and Ecology Laboratory, University of Burdwan RCV003128127 SCV003761534 likely risk allele Asthma 2022-11-04 no assertion criteria provided case-control 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.

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