ClinVar Miner

Submissions for variant NM_005373.2(MPL):c.378del (p.Phe126fs) (rs587778515)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255711 SCV000321907 pathogenic not provided 2016-08-29 criteria provided, single submitter clinical testing The c.378delT pathogenic variant in the MPL gene has been reported previously in association with congenital amegakaryocytic thrombocytopenia (CAMT) (Ballmaier et al., 2001). The deletion causes a frameshift starting with codon Phenylalanine 126, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Phe126LeufsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780430 SCV000917676 pathogenic Congenital amegakaryocytic thrombocytopenia 2018-06-22 criteria provided, single submitter clinical testing Variant summary: MPL c.378delT (p.Phe126LeufsX5) 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 4e-05 in 277158 control chromosomes. The variant, c.378delT, has been reported in the literature in multiple individuals affected with Congenital Amegakaryocytic Thrombocytopenia (Ballmaier_2001, Germeshausen_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000780430 SCV001162890 pathogenic Congenital amegakaryocytic thrombocytopenia criteria provided, single submitter clinical testing
Invitae RCV001047546 SCV001211511 pathogenic Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia 2020-10-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe126Leufs*5) in the MPL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587778515, ExAC 0.01%). This variant has been observed in several individuals affected with congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 28859041, 16470591). ClinVar contains an entry for this variant (Variation ID: 265249). Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). For these reasons, this variant has been classified as Pathogenic.
ITMI RCV000121537 SCV000085731 not provided not specified 2013-09-19 no assertion provided reference population
Natera, Inc. RCV000780430 SCV001453974 pathogenic Congenital amegakaryocytic thrombocytopenia 2020-09-16 no assertion criteria provided clinical testing

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