ClinVar Miner

Submissions for variant NM_005373.2(MPL):c.127C>T (p.Arg43Ter) (rs148434485)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411190 SCV000487190 pathogenic Congenital amegakaryocytic thrombocytopenia 2016-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778238 SCV000914406 pathogenic MPL-Related Disorders 2018-10-04 criteria provided, single submitter clinical testing The MPL c.127C>T (p.Arg43Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant has been reported in three studies in which it is identified in a total of six individuals with congenital amegakaryocytic thrombocytopenia, all with a severe phenotype, in one individual in a compound heterozygous state and in five individuals in a homozygous state (Ballmaier et al. 2001; Germeshausen et al. 2006; Savoia et al. 2007). The p.Arg43Ter variant has not been reported in individuals with essential thrombocythemia. The p.Arg43Ter variant was absent from 50 controls and is reported at a frequency of 0.000041 in the total population of the Exome Aggregation Consortium. Savoia et al. (2007) demonstrated that platelet surface expression of other glycoproteins was normal in one individual carrying the variant but MPL expression was scarcely detectable. Serum TPO levels were elevated and in colony-forming unit assays, platelet c-MPL and bone marrow colonies were reduced. Based on the evidence and potential impact of stop-gained variants, the p.Arg43Ter variant is classified as pathogenic for MPL-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001248333 SCV001421808 pathogenic Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia 2019-11-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg43*) in the MPL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs148434485, ExAC 0.02%). This variant has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 16470591). ClinVar contains an entry for this variant (Variation ID: 371574). Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). For these reasons, this variant has been classified as Pathogenic.

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