Submissions for variant NM_005373.3(MPL):c.305G>C (p.Arg102Pro)

gnomAD frequency: 0.00035  dbSNP: rs28928907

Total submissions: 16

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 thrombocythemia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 102 of the MPL protein (p.Arg102Pro). This variant is present in population databases (rs28928907, gnomAD 0.07%). This missense change has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (CAMT) (PMID: 971406, 11972523, 16470591, 18240171, 19302922, 21225925, 24119002, 26854587, 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: 14158). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MPL protein function. Experimental studies have shown that this missense change affects MPL function (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: 16470591, 21659346), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001091414	SCV001247446	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001091414	SCV001780753	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	Observed with a second MPL variant in additional patients with congenital amegakaryocytic thrombocytopenia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (van den Oudenrijn et al., 2000; Fox et al., 2009; Turro et al., 2020); Identified in the heterozygous state in members of a single family with mild thrombocytosis and/or elevated thrombopoietin levels (Bellann-Chantelot et al., 2017); Published functional studies demonstrate a damaging effect due to impaired subcellular distribution, impaired glycosylation, and lack of JAK/STAT pathway activation (Stockklausner et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 23351976, 27418648, 28034873, 32703794, 18422784, 16470591, 11133753, 15374889, 20188141, 26854587, 26556299, 28955303, 30431218, 30523342, 31589614, 35150448, 34308104, 28859041, 25538044, 24119002, 31064749, 28979237, 32581362, 10971406, 19302922)
Revvity Omics, Revvity	RCV001091414	SCV002017532	pathogenic	not provided	2023-03-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001091414	SCV002069553	pathogenic	not provided	2021-10-14	criteria provided, single submitter	clinical testing	This sequence has been previously described in multiple patients with congenital amegakaryocytic thrombocytopenia (CAMT) in both homozygous and compound heterozygous states with other pathogenic variants in the same gene (PMIDs: 11972523, 28859041, 16470591, 18240171, 19302922, 21225925, 24119002, 26854587). Functional studies have shown that this sequence change impairs trafficking and glycosylation of the receptor expressed at the cell surface (PMIDs: 19302922, 24438083, 25538044). This sequence change has been described in the gnomAD database with a population frequency of 0.071% in non-Finnish Europeans; however, it has not been observed in homozygous state in any individuals (dbSNP rs28928907). The p.Arg102Pro change affects a highly conserved amino acid residue located in the extracellular domain of the MPL protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg102Pro substitution. These collective evidences indicate that this sequence change is pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490372	SCV002798043	pathogenic	Congenital amegakaryocytic thrombocytopenia; Primary myelofibrosis; Thrombocythemia 2	2022-01-31	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000015221	SCV003921801	pathogenic	Congenital amegakaryocytic thrombocytopenia	2020-11-05	criteria provided, single submitter	clinical testing	0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with recessive congenital amegakaryocytic thrombocytopenia (CAMT) (MIM#604498) and dominant thrombocythemia 2 (MIM#601977), respectively (PMIDs: 28955303, 26423830). (I) 0108 - This gene is associated with autosomal dominant and recessive disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (107 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (9 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ligand binding domain (PDB, NCBI). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg102Cys) variant has been reported in multiple times, once as pathogenic in a patient with congenital amegakaryocytic thrombocytopenia (CAMT) (ClinVar) and several times in homozygous individuals with CAMT (PMIDs: 25539746, 21659346). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and observed in multiple individuals with autosomal recessive CAMT (ClinVar, PMIDs: 26854587, 21225925, 11972523). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies using transfected human cells showed MPL protein localisation and phosphorylation of signaling proteins were impaired (PMIDs: 28034873, 18422784). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091414	SCV001954125	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001091414	SCV001969196	pathogenic	not provided		no assertion criteria provided	clinical testing