Submissions for variant NM_005373.3(MPL):c.189C>A (p.Tyr63Ter)

dbSNP: rs1373623383

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174802	SCV001338148	likely pathogenic	Congenital amegakaryocytic thrombocytopenia	2020-02-10	criteria provided, single submitter	clinical testing	Variant summary: MPL c.189C>A (p.Tyr63X) 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 was absent in 251164 control chromosomes (gnomAD). c.189C>A has been reported in the literature in compound heterozygous individuals affected with Congenital Amegakaryocytic Thrombocytopenia (Savoia_2007, Chung_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001819878	SCV002068996	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MPL gene demonstrated a sequence change, c.189C>A, which results in the creation of a premature stop codon at amino acid position 63, p.Tyr63*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MPL protein with potentially abnormal function. This pathogenic sequence change has previously been described in the compound heterozygous state in a patient with congenital amegakaryocytic thrombocytopenia (Chung et. al., 2011). This pathogenic sequence change in the heterozygous state is not sufficient to cause this patient's thrombocytopenia. This patient is a germline carrier of this sequence change. Heterozygous germline or somatic pathogenic variants in the MPL gene have been described in the patients with thrombocythemia [OMIM#601977]. Somatic pathogenic variants in MPL also cause myelofibrosis [OMIM#254450]. Homozygous or compound heterozygous pathogenic variants in the MPL gene have been described in the patients with congenital amegakaryocytic thrombocytopenia [OMIM#604498].
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769858	SCV004574544	pathogenic	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2023-03-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr63*) in the MPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive MPL-related conditions (PMID: 17666371, 21162090). ClinVar contains an entry for this variant (Variation ID: 917671).