NM_005373.3(MPL):c.1621C>T (p.Gln541Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 14, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001854660.4

Allele description [Variation Report for NM_005373.3(MPL):c.1621C>T (p.Gln541Ter)]

NM_005373.3(MPL):c.1621C>T (p.Gln541Ter)

Gene:

MPL:MPL proto-oncogene, thrombopoietin receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.2

Genomic location:

Preferred name:

NM_005373.3(MPL):c.1621C>T (p.Gln541Ter)

HGVS:

NC_000001.11:g.43352271C>T
NG_007525.1:g.19468C>T
NM_005373.2:c.1621C>T
NM_005373.3:c.1621C>TMANE SELECT
NP_005364.1:p.Gln541Ter
LRG_510:g.19468C>T
NC_000001.10:g.43817942C>T

Protein change:

Q541*

Links:

dbSNP: rs369156948

NCBI 1000 Genomes Browser:

rs369156948

Molecular consequence:

NM_005373.3:c.1621C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Congenital amegakaryocytic thrombocytopenia
Identifiers:: MONDO: MONDO:0800451; MedGen: C1327915; Orphanet: 3319; OMIM: PS604498

Name:: Essential thrombocythemia
Synonyms:: essential thrombocytemia; Suspected essential thromboythemia
Identifiers:: MONDO: MONDO:0005029; MeSH: D013920; MedGen: C0040028

Recent activity

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Homo sapiens HLA-B gene for MHC class I antigen, B*5301 allele, intron 4
Homo sapiens HLA-B gene for MHC class I antigen, B*5301 allele, intron 4
gi|10045138|emb|AJ294499.1|

Nucleotide
Influenza B virus (B/Tennessee/UR06-0431/2007) segment 4, complete sequence
Influenza B virus (B/Tennessee/UR06-0431/2007) segment 4, complete sequence
gi|169731736|gnl|NIGSP|NIGSP-SDI-04 A|gb|CY030657.1|

Nucleotide
LGI1 [Callithrix jacchus]
LGI1 [Callithrix jacchus]
Gene ID:100415038

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002217130	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19302922, 23625800, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002217130

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 14, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Compound heterozygous c-Mpl mutations in a child with congenital amegakaryocytic thrombocytopenia: functional characterization and a review of the literature.

Fox NE, Chen R, Hitchcock I, Keates-Baleeiro J, Frangoul H, Geddis AE.

Exp Hematol. 2009 Apr;37(4):495-503. doi: 10.1016/j.exphem.2009.01.001. Review.

PubMed [citation]

PMID:: 19302922
PMCID:: PMC2694734

Congenital amegakaryocytic thrombocytopenia (CAMT) presenting as severe pancytopenia in the first month of life.

Stoddart MT, Connor P, Germeshausen M, Ballmaier M, Steward CG.

Pediatr Blood Cancer. 2013 Sep;60(9):E94-6. doi: 10.1002/pbc.24566. Epub 2013 Apr 26.

PubMed [citation]

PMID:: 23625800

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002217130.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Gln541*) in the MPL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the MPL protein. This variant is present in population databases (rs369156948, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital amegakaryocytic thrombocytopenia (PMID: 19302922). ClinVar contains an entry for this variant (Variation ID: 134819). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MPL protein in which other variant(s) (p.Lys553Argfs*77) have been determined to be pathogenic (PMID: 23625800; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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