ClinVar Miner

Submissions for variant NM_005373.3(MPL):c.268C>T (p.Arg90Ter)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001229853 SCV001402313 pathogenic Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia 2020-08-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg90*) in the MPL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs763144679, ExAC 0.009%). This variant has been observed in an individual affected with autosomal recessive congenital amegakaryocytic thrombocytopenia (PMID: 11133753). 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 RCV001251410 SCV001427000 pathogenic Congenital amegakaryocytic thrombocytopenia 2020-07-27 criteria provided, single submitter clinical testing Variant summary: MPL c.268C>T (p.Arg90X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes (gnomAD). c.268C>T has been reported in the literature in multiple individuals affected with Congenital Amegakaryocytic Thrombocytopenia (Ballmaier_2001, Newman_2017). These data indicate that the variant is very likely to be associated with disease. One of these publications also reported experimental evidence evaluating an impact on protein function, and demonstrated impaired growth of megakaryocytic- and also of myeloid and erythroid colonies in colony-forming assays performed on bone marrow mononuclear cells derived from a homozygous patient (Ballmaier_2001). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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