ClinVar Miner

Submissions for variant NM_005373.2(MPL):c.754T>C (p.Tyr252His) (rs141311765)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ITMI RCV000121549 SCV000085743 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000778239 SCV000914407 uncertain significance Congenital amegakaryocytic thrombocytopenia 2017-04-27 criteria provided, single submitter clinical testing The MPL c.754T>C (p.Tyr252His) missense variant has been reported in one study in which it was identified in a heterozygous state in a child with essential thrombocythemia (Lambert et al. 2012). The patient also carried two other variants in the MPL gene in a heterozygous state, one of which was a known polymorphism and the other was found deep in an intron and thought unlikely to be responsible for the phenotype. The variant has not been reported in individuals with congenital amegakaryocytic thrombocytopenia. Control data are unavailable for the p.Tyr252His variant which is reported at a frequency of 0.0052 in the African American population of the Exome Sequencing Project. The Tyr252 residue is noted to be conserved. Wild type and variant MPL were introduced into cytokine-dependent BaF3 cells through retroviral transduction. Cells stably expressing the p.Tyr252His variant allele exhibited increased proliferation in response to thrombopoietin (TPO), in particular at low concentration, when compared to wild type. Upon cytokine withdrawal, cells expressing the variant survived better than those expressing a wild type allele. These data suggest that the p.Tyr252His variant results in increased TPO/MPL-mediated cell growth and may contribute to the development of essential thrombocythemia in vivo (Lambert et al. 2012). In a genome wide association study of nearly 15,000 African Americans, the p.Tyr252His variant was significantly associated with higher platelet counts (Auer et al. 2012). Based on the limited evidence, the p.Tyr152His variant is classified as a variant of unknown significance for essential thrombocythemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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