NM_005373.3(MPL):c.1514G>A (p.Ser505Asn) AND Thrombocythemia 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 8, 2009
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000015226.27

Allele description [Variation Report for NM_005373.3(MPL):c.1514G>A (p.Ser505Asn)]

NM_005373.3(MPL):c.1514G>A (p.Ser505Asn)

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.1514G>A (p.Ser505Asn)

HGVS:

NC_000001.11:g.43349308G>A
NG_007525.1:g.16505G>A
NM_005373.3:c.1514G>AMANE SELECT
NP_005364.1:p.Ser505Asn
LRG_510:g.16505G>A
NC_000001.10:g.43814979G>A
P40238:p.Ser505Asn

Protein change:

S505N; SER505ASN

Links:

UniProtKB: P40238#VAR_067559; OMIM: 159530.0010; dbSNP: rs121913614

NCBI 1000 Genomes Browser:

rs121913614

Molecular consequence:

NM_005373.3:c.1514G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Thrombocythemia 2
Synonyms:: Thrombocytosis, benign familial microcytic; THROMBOCYTHEMIA 2, SUSCEPTIBILITY TO
Identifiers:: MONDO: MONDO:0011173; MedGen: C3275998; OMIM: 601977

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035484	OMIM	no assertion criteria provided	Pathogenic (Oct 8, 2009)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 14764528, 19483125

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035484

OMIM

no assertion criteria provided

Pathogenic
(Oct 8, 2009)

germline

literature only

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin.

Ding J, Komatsu H, Wakita A, Kato-Uranishi M, Ito M, Satoh A, Tsuboi K, Nitta M, Miyazaki H, Iida S, Ueda R.

Blood. 2004 Jun 1;103(11):4198-200. Epub 2004 Feb 5.

PubMed [citation]

PMID:: 14764528

The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity.

Ding J, Komatsu H, Iida S, Yano H, Kusumoto S, Inagaki A, Mori F, Ri M, Ito A, Wakita A, Ishida T, Nitta M, Ueda R.

Blood. 2009 Oct 8;114(15):3325-8. doi: 10.1182/blood-2008-04-149047. Epub 2009 May 29.

PubMed [citation]

PMID:: 19483125

Details of each submission

From OMIM, SCV000035484.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In affected members of a Japanese family with autosomal dominant thrombocythemia-2 (THCYT2; 601977), Ding et al. (2004) identified a heterozygous 1073G-A transition in exon 10 of the MPL gene, resulting in a ser505-to-asn (S505N) substitution. Cellular studies showed that mutant cells had increased cytokine-independent survival and constitutively phosphorylated Mek1/2 (see, e.g., 176872), suggesting that S505N is an activating mutation.

Variant Function

Ding et al. (2009) found that, due to the strong polarity of asparagine, the S505N substitution induced autonomous dimerization of mutant MPL, permitting signal activation in the absence of ligand.

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

Last Updated: Sep 3, 2023

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