ClinVar Miner

Submissions for variant NM_005373.2(MPL):c.1069C>T (p.Arg357Ter) (rs751975712)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000818204 SCV000958804 pathogenic Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia 2020-08-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg357*) in the MPL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs751975712, ExAC 0.01%). This variant has been observed in individuals affected with congenital amegakaryocytic thrombocytopenia (PMID: 21162090, 29384262). ClinVar contains an entry for this variant (Variation ID: 660904). Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420932 SCV001623391 pathogenic Congenital amegakaryocytic thrombocytopenia 2021-04-29 criteria provided, single submitter clinical testing Variant summary: MPL c.1069C>T (p.Arg357X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251476 control chromosomes. c.1069C>T has been reported in the literature in individuals affected with Congenital Amegakaryocytic Thrombocytopenia (e.g. Chung_2011, Liu_2018, Germeshausen_2020). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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