NM_005373.3(MPL):c.317C>T (p.Pro106Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 25, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000255329.16

Allele description [Variation Report for NM_005373.3(MPL):c.317C>T (p.Pro106Leu)]

NM_005373.3(MPL):c.317C>T (p.Pro106Leu)

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.317C>T (p.Pro106Leu)

HGVS:

NC_000001.11:g.43338646C>T
NG_007525.1:g.5843C>T
NM_005373.3:c.317C>TMANE SELECT
NP_005364.1:p.Pro106Leu
NP_005364.1:p.Pro106Leu
LRG_510t1:c.317C>T
LRG_510:g.5843C>T
LRG_510p1:p.Pro106Leu
NC_000001.10:g.43804317C>T
NM_005373.2:c.317C>T
NM_005373.3:c.317C>T
P40238:p.Pro106Leu

Protein change:

P106L

Links:

UniProtKB: P40238#VAR_073033; dbSNP: rs750046020

NCBI 1000 Genomes Browser:

rs750046020

Molecular consequence:

NM_005373.3:c.317C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321906	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 6, 2023)	germline	clinical testing	Citation Link,
SCV002023507	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002069100	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 19, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321906

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 6, 2023)

germline

clinical testing

Citation Link,

SCV002023507

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 25, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002069100

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 19, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000321906.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

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

From Revvity Omics, Revvity, SCV002023507.3

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

#	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

From Genetic Services Laboratory, University of Chicago, SCV002069100.1

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

Description

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.

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

Last Updated: May 19, 2024

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