NM_005373.3(MPL):c.391+5G>C AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 23, 2022
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:: RCV000414099.12

Allele description [Variation Report for NM_005373.3(MPL):c.391+5G>C]

NM_005373.3(MPL):c.391+5G>C

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.391+5G>C

HGVS:

NC_000001.11:g.43338725G>C
NG_007525.1:g.5922G>C
NM_005373.3:c.391+5G>CMANE SELECT
LRG_510t1:c.391+5G>C
LRG_510:g.5922G>C
NC_000001.10:g.43804396G>C
NM_005373.2:c.391+5G>C

Links:

dbSNP: rs752453717

NCBI 1000 Genomes Browser:

rs752453717

Molecular consequence:

NM_005373.3:c.391+5G>C - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000490615	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 23, 2022)	germline	clinical testing	Citation Link,
SCV002067317	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 12, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003819608	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2022)	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

SCV000490615

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 23, 2022)

germline

clinical testing

Citation Link,

SCV002067317

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 12, 2019)

germline

clinical testing

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

SCV003819608

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 1, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	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, SCV000490615.5

#	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 resulting in inefficient splicing and diminished protein expression (Gandhi et al, 2005); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 26369627, 19388932, 22102270, 11972523, 32703794, 31589614, 33572923, 16219544)

#	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 Genetic Services Laboratory, University of Chicago, SCV002067317.1

#	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 PARN gene demonstrated a sequence change located near the canonical splice donor site in intron 3, c.391+5G>C. This sequence change has been previously described in three siblings with late presentation of congenital amegakaryocytic thrombocytopenia in a biallelic state with a frameshift pathogenic variant (PMID: 16219544). In vitro functional studies have shown that this variant leads to inefficient splicing at exon 3 and has an impact on MPL expression and function compared to the wildtype MPL. This sequence change has been described in the gnomAD database with a low population frequency of 0.023% in non-Finnish subpopulation (dbSNP rs752453717). The presence of this sequence change together with the truncating variant described above is suggestive of this variant being likely pathogenic.

#	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, SCV003819608.2

#	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

Last Updated: Sep 29, 2024

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