ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ITMI RCV000121539 SCV000085733 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000792211 SCV000931491 pathogenic Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia 2018-12-24 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. Additionally, this variant has been observed in the heterozygous state in a family affected with thrombocytosis (PMID: 28979237). 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852103 SCV000899661 pathogenic Thrombocytopenia 2019-02-01 criteria provided, single submitter research
OMIM RCV000015221 SCV000035479 pathogenic Congenital amegakaryocytic thrombocytopenia 2008-06-01 no assertion criteria provided literature only

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