ClinVar Genomic variation as it relates to human health
NM_005373.3(MPL):c.317C>T (p.Pro106Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005373.3(MPL):c.317C>T (p.Pro106Leu)
Variation ID: 265248 Accession: VCV000265248.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 43338646 (GRCh38) [ NCBI UCSC ] 1: 43804317 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005373.3:c.317C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005364.1:p.Pro106Leu missense NC_000001.11:g.43338646C>T NC_000001.10:g.43804317C>T NG_007525.1:g.5843C>T LRG_510:g.5843C>T LRG_510t1:c.317C>T LRG_510p1:p.Pro106Leu P40238:p.Pro106Leu - Protein change
- P106L
- Other names
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- Canonical SPDI
- NC_000001.11:43338645:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MPL | - | - |
GRCh38 GRCh37 |
742 | 755 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 25, 2023 | RCV000255329.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV000814672.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 14, 2023 | RCV001731468.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 22, 2022 | RCV002250607.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2021 | RCV002479991.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2024 | RCV003992253.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2024 | RCV003955416.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Nov 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Thrombocythemia 2
Affected status: yes
Allele origin:
germline
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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984330.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Likely pathogenic
(Jul 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002069100.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the MPL gene demonstrated a sequence change, c.317C>T, in exon 3 that results in an amino acid change, p.Pro106Leu. This sequence … (more)
DNA sequence analysis of the MPL gene demonstrated a sequence change, c.317C>T, in exon 3 that results in an amino acid change, p.Pro106Leu. This sequence change has been described in the EXAC database with a low population frequency of 0.005% (dbSNP rs750046020) and has previously been described in patients with familial thrombocytosis in the homozygous state (El-Harith el-HA, et al., 2009; Stockklausner C, et al., 2012). Heterozygous carriers presented with normal platelet counts or mild thrombocytosis (El-Harith el-HA, et al., 2009; Stockklausner C, et al., 2012). The p.Pro106Leu change affects a highly conserved amino acid residue located in a 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.Pro106Leu substitution. (less)
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Likely pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital amegakaryocytic thrombocytopenia 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002520973.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Same nucleotide change resulting in same amino … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265248). The variant has been observed in multiple, similarly affected unrelated individuals (PMID: 19036112). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Thrombocytosis (present)
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Likely pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary myelofibrosis
Thrombocythemia 2 Congenital amegakaryocytic thrombocytopenia 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002800513.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321906.10
First in ClinVar: Oct 10, 2016 Last updated: Jul 08, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with abnormal subcellular distribution of receptors and impaired glycosylation (Stockklausner et al, 2015); In silico analysis supports that … (more)
Published functional studies demonstrate a damaging effect with abnormal subcellular distribution of receptors and impaired glycosylation (Stockklausner et al, 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28034873, 30553997, 23351976, 31589614, 34308104, 35791502, 31135094, 35112413, 26077850, 28955303, 28979237, 28408900, 30318940, 30996850, 31092065, 30183354, 31808840, 33777803, 28444727, 33712866, 27884173, Mutairi_article_2023, 25538044, 34131895, 19036112) (less)
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Pathogenic
(Nov 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Thrombocythemia 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004101784.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
MPL, a transmembrane protein receptor, is frequently mutated in myeloproliferative neoplasms including essential thrombocytosis and myelofibrosis. The MPL P106L mutation previously reported as pathogenic/likely pathogenic … (more)
MPL, a transmembrane protein receptor, is frequently mutated in myeloproliferative neoplasms including essential thrombocytosis and myelofibrosis. The MPL P106L mutation previously reported as pathogenic/likely pathogenic with strong evidence in ClinVar, The p.Pro106Leu change affects a highly conserved amino acid residue located in a domain of the MPL protein that is known to be functional. In-silico pathogenicity prediction tools, The presence of a MPL P106L mutation strongly supports a diagnosis of essential thrombocythemia.This variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Sep 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023507.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Essential thrombocythemia
Congenital amegakaryocytic thrombocytopenia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000955091.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 106 of the MPL protein (p.Pro106Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 106 of the MPL protein (p.Pro106Leu). This variant is present in population databases (rs750046020, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive MPL-related conditions (PMID: 19036112, 25538044). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265248). 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: 25538044). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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MPL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004770411.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The MPL c.317C>T variant is predicted to result in the amino acid substitution p.Pro106Leu. This variant has a minor allele frequency of up to 2.6% … (more)
The MPL c.317C>T variant is predicted to result in the amino acid substitution p.Pro106Leu. This variant has a minor allele frequency of up to 2.6% in Saudi Arabians (Abouelhoda et al. 2016. PubMed ID: 27884173. Table S5), and is a frequent MPL pathogenic variant in the Arab population, leading to thrombocytosis in homozygotes and occasionally mild thrombocytosis in some heterozygous carriers (El-Harith et al. 2009. PubMed ID: 19036112). Functional analyses suggest that the MPL p.Pro106Leu change causes thrombocytosis due to an incomplete trafficking defect (Stockklausner et al. 2015. PubMed ID: 25538044). Expression of the variant MPL protein in vivo in mice partially reproduced the phenotype observed in homozygous patients (Favale et al. 2016. PubMed ID: 28034873). This variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital amegakaryocytic thrombocytopenia 1
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810068.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs750046020 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.