1-43338634-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM5PP2PP5_Very_Strong

The NM_005373.3(MPL):c.305G>C(p.Arg102Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000455 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

MPL
NM_005373.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 5.43

Publications

48 publications found

Variant links:

Genes affected

MPL (HGNC:7217): (MPL proto-oncogene, thrombopoietin receptor) In 1990 an oncogene, v-mpl, was identified from the murine myeloproliferative leukemia virus that was capable of immortalizing bone marrow hematopoietic cells from different lineages. In 1992 the human homologue, named, c-mpl, was cloned. Sequence data revealed that c-mpl encoded a protein that was homologous with members of the hematopoietic receptor superfamily. Presence of anti-sense oligodeoxynucleotides of c-mpl inhibited megakaryocyte colony formation. The ligand for c-mpl, thrombopoietin, was cloned in 1994. Thrombopoietin was shown to be the major regulator of megakaryocytopoiesis and platelet formation. The protein encoded by the c-mpl gene, CD110, is a 635 amino acid transmembrane domain, with two extracellular cytokine receptor domains and two intracellular cytokine receptor box motifs . TPO-R deficient mice were severely thrombocytopenic, emphasizing the important role of CD110 and thrombopoietin in megakaryocyte and platelet formation. Upon binding of thrombopoietin CD110 is dimerized and the JAK family of non-receptor tyrosine kinases, as well as the STAT family, the MAPK family, the adaptor protein Shc and the receptors themselves become tyrosine phosphorylated. [provided by RefSeq, Jul 2008]

MPL Gene-Disease associations (from GenCC):

thrombocythemia 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
congenital amegakaryocytic thrombocytopenia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
congenital amegakaryocytic thrombocytopenia 1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
familial thrombocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary isolated aplastic anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005373.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-43338633-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 644406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.39478 (below the threshold of 3.09). Trascript score misZ: 1.6963 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary isolated aplastic anemia, congenital amegakaryocytic thrombocytopenia, thrombocythemia 2, congenital amegakaryocytic thrombocytopenia 1, familial thrombocytosis.

PP5

Variant 1-43338634-G-C is Pathogenic according to our data. Variant chr1-43338634-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3 link	c.305G>C	p.Arg102Pro	missense_variant	Exon 3 of 12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MPL	ENST00000372470.9 link	c.305G>C	p.Arg102Pro	missense_variant	Exon 3 of 12	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7 link	c.284G>C	p.Arg95Pro	missense_variant	Exon 3 of 12	1		ENSP00000414004.3
MPL	ENST00000638732.1 link	n.305G>C		non_coding_transcript_exon_variant	Exon 3 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000382

AC:

AN:

251490

AF XY:

0.000390

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000475

AC:

694

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000469

AC XY:

341

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000589

AC:

655

AN:

1112006

Other (OTH)

AF:

0.000315

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000263

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41544

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68002

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000380

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:10

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MPL c.305G>C; p.Arg102Pro variant (rs28928907) is reported in the literature as a homozygous and compound heterozygous pathogenic germline variant associated with autosomal recessive type II congenital amegakaryocytic thrombocytopenia (Eshuis-Peters) (van den Oudenrijn) (van den Oudenrijn) (Woods). In addition, one study reported elevated thrombopoietin and thrombocytosis in a family where this variant was detected in the heterozygous state (Bellanne-Chantelot). This variant is reported in ClinVar (Variation ID: 14158). This variant is found in the general population with an overall allele frequency of 0.04% (107/282858 alleles, including zero homozygotes) in the Genome Aggregation Database (v2.1.1). In vitro studies demonstrate reduced MPL signaling as well as abnormal subcellular MPL receptor distribution, lack of membrane localization, and impaired glycosylation (Stockklausner) (Tijssen). Based on available information, this variant is considered to be pathogenic. References: Bellanne-Chantelot C et al. Identification of MPL R102P Mutation in Hereditary Thrombocytosis. Front Endocrinol (Lausanne). 2017 PMID: 28979237. Eshuis-Peters E et al. Congenital Amegakaryocytic Thrombocytopenia Type II Presenting with Multiple Central Nervous System Anomalies. Neuropediatrics. 2016 Apr. PMID: 26854587.Stockklausner C et al. The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis. Blood. 2015 Feb 12. PMID: 25538044. Tijssen MR et al. Functional analysis of single amino-acid mutations in the thrombopoietin-receptor Mpl underlying congenital amegakaryocytic thrombocytopenia. Br J Haematol. 2008 Jun. PMID: 18422784. van den Oudenrijn S et al. Three parameters, plasma thrombopoietin levels, plasma glycocalicin levels and megakaryocyte culture, distinguish between different causes of congenital thrombocytopenia. Br J Haematol. 2002 May. PMID: 11972523. van den Oudenrijn S et al. Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia. Br J Haematol. 2000 Aug. PMID: 10971406. Woods G et al. Reduced intensity transplantation for congenital amegakaryocytic thrombocytopenia: report of a case and review of the literature. Pediatr Transplant. 2014 Feb. PMID: 24119002 -

Aug 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PM3_strong, PM5, PS3, PS4 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 05, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 27, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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 (PMID: 19302922, 32581362, 10971406); Identified in the heterozygous state in members of a single family with mild thrombocytosis and/or elevated thrombopoietin levels (PMID: 28979237); Published functional studies demonstrate a damaging effect due to impaired subcellular distribution, impaired glycosylation, and lack of JAK/STAT pathway activation (PMID: 25538044); In silico analysis indicates 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, 37939832, 35776903, 32191290, 35150448, 34308104, 28859041, 24119002, 31064749, 32581362, 10971406, 19302922, 38752375, 37647632, 25538044, 28979237) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MPL: PM3:Very Strong, PM2, PM5, PS3:Supporting -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2021

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Congenital amegakaryocytic thrombocytopenia 1

Pathogenic:4

Jun 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 22, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 25, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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 -

Congenital amegakaryocytic thrombocytopenia

Pathogenic:3

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 17, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary myelofibrosis;C3275998:Thrombocythemia 2;C5882667:Congenital amegakaryocytic thrombocytopenia 1

Pathogenic:1

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thrombocytopenia

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia

Pathogenic:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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 autosomal recessive 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). Invitae Evidence 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 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. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

5.4

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.3

N;.

REVEL

Uncertain

0.52

Sift

Benign

0.082

T;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.93

MVP

0.87

MPC

0.90

ClinPred

0.69

GERP RS

5.6

Varity_R

0.62

gMVP

0.88

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over