ClinVar Miner

Submissions for variant NM_005373.2(MPL):c.305G>C (p.Arg102Pro) (rs28928907)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000015221 SCV000698585 pathogenic Congenital amegakaryocytic thrombocytopenia 2017-04-17 criteria provided, single submitter clinical testing Variant summary: The MPL c.305G>C (p.Arg102Pro) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 56/121606 control chromosomes at a frequency of 0.0004605, which does not exceed the estimated maximal expected allele frequency of a pathogenic MPL variant (0.002357). The variant was reported in numerous CAMPT patients in the literature, both in the homozygous and compound heterozygous state. Functional studies have shown the variant to lead to abnormal subcellular receptor distribution, lack of membrane localization, impaired glycosylation as well as impaired TPO signal transduction (Stockklausner_2015, Tijssen_2008). Taken together, this variant is classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852103 SCV000899661 pathogenic Thrombocytopenia 2019-02-01 criteria provided, single submitter research
Invitae RCV000792211 SCV000931491 pathogenic Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia 2020-10-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 102 of the MPL protein (p.Arg102Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs28928907, ExAC 0.08%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with congenital amegakaryocytic thrombocytopenia (CAMT) (PMID: 11972523, 28859041). This variant has also been observed to be homozygous or in combination with another MPL variant in several individuals affected with CAMT (PMID: 10971406, 16470591, 18240171, 19302922, 21225925, 24119002, 26854587). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 14158). Experimental studies have shown that this missense change impairs trafficking of the receptor to the cell surface, glycosylation of the protein, and proliferative responses to thrombopoietin (PMID: 18422784, 19302922, 24438083, 25538044). This variant disrupts the p.Arg102 amino acid residue in MPL. Other variant(s) that disrupt this residue have been observed in individuals with MPL-related conditions (PMID: 21659346, 16470591), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091414 SCV001247446 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
GeneDx RCV001091414 SCV001780753 pathogenic not provided 2020-12-07 criteria provided, single submitter clinical testing Identified in a patient in published literature with congenital amegakaryocytic thrombocytopenia (van den Oudenrijn et al., 2000); Published functional studies demonstrate a damaging effect (impaired subcellular distribution, impaired glycosylation, and lack of JAK/STAT pathway activation) (Stockklausner et al., 2015); This variant is associated with the following publications: (PMID: 31589614, 32581362, 31064749, 30523342, 30431218, 28859041, 27418648, 28955303, 28034873, 28979237, 26556299, 26854587, 25538044, 23351976, 20188141, 19302922, 15374889, 11133753, 16470591, 10971406, 24119002, 24728327, 18422784, 32703794)
OMIM RCV000015221 SCV000035479 pathogenic Congenital amegakaryocytic thrombocytopenia 2008-06-01 no assertion criteria provided literature only
ITMI RCV000121539 SCV000085733 not provided not specified 2013-09-19 no assertion provided reference population
NIHR Bioresource Rare Diseases, University of Cambridge RCV000015221 SCV001161805 likely pathogenic Congenital amegakaryocytic thrombocytopenia no assertion criteria provided research
Natera, Inc. RCV000015221 SCV001453972 pathogenic Congenital amegakaryocytic thrombocytopenia 2020-09-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001091414 SCV001926461 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001091414 SCV001954125 pathogenic not provided no assertion criteria provided clinical testing

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