VCV000134822.17 - ClinVar

NM_005373.3(MPL):c.235_236del (p.Leu79fs)

Germline

Classification

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.

(8)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005373.3(MPL):c.235_236del (p.Leu79fs)

Variation ID: 134822 Accession: VCV000134822.17

Type and length

Deletion, 2 bp

Location

Cytogenetic: 1p34.2 1: 43338564-43338565 (GRCh38) [ NCBI UCSC ] 1: 43804235-43804236 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jun 9, 2014	Feb 28, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005373.3:c.235_236del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005364.1:p.Leu79fs	frameshift
NM_005373.2:c.235_236delCT
NC_000001.11:g.43338564_43338565del
NC_000001.10:g.43804235_43804236del
NG_007525.1:g.5761_5762del
LRG_510:g.5761_5762del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:43338563:CT:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00005

The Genome Aggregation Database (gnomAD) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00005

Links

ClinGen: CA160816 dbSNP: rs587778514 VarSome

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
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
MPL		-	-	GRCh38 GRCh37	755	769

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 Help 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.
not specified	not provided (1)	no classification provided	Sep 19, 2013	RCV000121536.4
Congenital amegakaryocytic thrombocytopenia	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 18, 2017	RCV000503692.10
Congenital amegakaryocytic thrombocytopenia Essential thrombocythemia	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2024	RCV000818190.9
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 4, 2022	RCV002281948.3
Congenital amegakaryocytic thrombocytopenia Primary myelofibrosis Thrombocythemia 2	Pathogenic (1)	criteria provided, single submitter	May 2, 2022	RCV002498569.2

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.
Pathogenic (Jan 12, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital amegakaryocytic thrombocytopenia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698584.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017	Publications: PubMed (4) PubMed: 11133753‚ 17666371‚ 27418648‚ 16470591 Comment: Variant summary: The MPL c.235_236delCT (p.Leu79Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent MPL protein due to nonsense … (more) Variant summary: The MPL c.235_236delCT (p.Leu79Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent MPL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 6/121376 control chromosomes at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic MPL variant (0.002357). The variant has been reported in affected individuals in the literature in the homozygous and compound heterozygous state. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Sep 04, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002571542.2 First in ClinVar: Sep 17, 2022 Last updated: Mar 04, 2023	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect of no protein expression (Gandhi et al., 2005); This variant is associated with the following publications: (PMID: 19388932, 17666371, 21228398, 16470591, 19302922, 31350202, 29625052, 34426522, 31589614, 11133753, 16219544) (less)
Pathogenic (Apr 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombocytopenia, congenital amegakaryocytic Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595824.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (May 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary myelofibrosis Thrombocythemia 2 Congenital amegakaryocytic thrombocytopenia 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002810459.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital amegakaryocytic thrombocytopenia 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047070.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The MPL c.235_236del (p.Leu79GlufsTer84) variant has been reported in homozygous state in individuals affected with Amegakaryocytic Thrombocytopenia, Congenital (Ballmaier M et al.). Experimental studies have … (more) The MPL c.235_236del (p.Leu79GlufsTer84) variant has been reported in homozygous state in individuals affected with Amegakaryocytic Thrombocytopenia, Congenital (Ballmaier M et al.). Experimental studies have shown that this frameshift predicted to result in a complete absence of functional c-Mpl protein. This variant has also been reported to lead to a complete loss of a functional TPO receptor c-Mpl (Ballmaier M et al.). This variant has been submitted with the allele frequency 0.005% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. This variant causes a frameshift starting with codon Leucine 79, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 84 of the new reading frame, denoted p.Leu79GlufsTer84. Loss-of-function variants in MPL are known to be pathogenic (Gurney AL et al.) For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Thrombocytopenia (present) , Pancytopenia (present) , Megakaryocytopenia (present)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000958789.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 8073287‚ 11133753‚ 17666371 Comment: This sequence change creates a premature translational stop signal (p.Leu79Glufs84) in the MPL gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu79Glufs84) in the MPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). This variant is present in population databases (rs587778514, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 17666371). This variant is also known as del235/236. ClinVar contains an entry for this variant (Variation ID: 134822). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Congenital amegakaryocytic thrombocytopenia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453969.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085730.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic

Comment:

Variant summary: The MPL c.235_236delCT (p.Leu79Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent MPL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 6/121376 control chromosomes at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic MPL variant (0.002357). The variant has been reported in affected individuals in the literature in the homozygous and compound heterozygous state. Taken together, this variant is classified as pathogenic.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect of no protein expression (Gandhi et al., 2005); This variant is associated with the following publications: (PMID: 19388932, 17666371, 21228398, 16470591, 19302922, 31350202, 29625052, 34426522, 31589614, 11133753, 16219544)

Comment:

The MPL c.235_236del (p.Leu79GlufsTer84) variant has been reported in homozygous state in individuals affected with Amegakaryocytic Thrombocytopenia, Congenital (Ballmaier M et al.). Experimental studies have shown that this frameshift predicted to result in a complete absence of functional c-Mpl protein. This variant has also been reported to lead to a complete loss of a functional TPO receptor c-Mpl (Ballmaier M et al.). This variant has been submitted with the allele frequency 0.005% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. This variant causes a frameshift starting with codon Leucine 79, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 84 of the new reading frame, denoted p.Leu79GlufsTer84. Loss-of-function variants in MPL are known to be pathogenic (Gurney AL et al.) For these reasons, this variant has been classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Leu79Glufs*84) in the MPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). This variant is present in population databases (rs587778514, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 17666371). This variant is also known as del235/236. ClinVar contains an entry for this variant (Variation ID: 134822). For these reasons, this variant has been classified as Pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients.	Keel SB	Haematologica	2016	PMID: 27418648
Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations.	Savoia A	Haematologica	2007	PMID: 17666371
MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: the type of mutation predicts the course of the disease.	Germeshausen M	Human mutation	2006	PMID: 16470591
c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia.	Ballmaier M	Blood	2001	PMID: 11133753
Thrombocytopenia in c-mpl-deficient mice.	Gurney AL	Science (New York, N.Y.)	1994	PMID: 8073287

Text-mined citations for rs587778514 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005373.3(MPL):c.235_236del (p.Leu79fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587778514 ...