ClinVar Miner

Submissions for variant NM_005373.3(MPL):c.769C>T (p.Arg257Cys)

gnomAD frequency: 0.00011  dbSNP: rs121913611
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001038272 SCV001201736 pathogenic Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia 2021-11-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 257 of the MPL protein (p.Arg257Cys). This variant is present in population databases (rs121913611, gnomAD 0.009%). This missense change has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (PMID: 10971406, 28859041). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 14156). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MPL function (PMID: 18422784, 20188141). This variant disrupts the p.Arg257 amino acid residue in MPL. Other variant(s) that disrupt this residue have been observed in individuals with MPL-related conditions (PMID: 16470591), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000015219 SCV001774496 pathogenic Congenital amegakaryocytic thrombocytopenia 2021-07-27 criteria provided, single submitter clinical testing Variant summary: MPL c.769C>T (p.Arg257Cys) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250774 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MPL causing Congenital Amegakaryocytic Thrombocytopenia (6e-05 vs 0.0024), allowing no conclusion about variant significance. c.769C>T has been reported in the literature in individuals affected with Congenital Amegakaryocytic Thrombocytopenia (example, VandenOudenrijn_2000, Lo_2018, Andres_2018). These data indicate that the variant is 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 impaired signal transduction (Tijssen_2008). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Services Laboratory,University of Chicago RCV001818159 SCV002069058 likely pathogenic not provided 2017-12-28 criteria provided, single submitter clinical testing
OMIM RCV000015219 SCV000035477 pathogenic Congenital amegakaryocytic thrombocytopenia 2008-06-01 no assertion criteria provided literature only
Natera, Inc. RCV000015219 SCV001453980 pathogenic Congenital amegakaryocytic thrombocytopenia 2020-09-16 no assertion criteria provided clinical testing

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