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NM_005373.3(MPL):c.79+2T>A AND MPL-related disorder

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jan 20, 2024
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:
RCV000778237.7

Allele description

NM_005373.3(MPL):c.79+2T>A

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.79+2T>A
HGVS:
  • NC_000001.11:g.43337929T>A
  • NG_007525.1:g.5126T>A
  • NM_005373.3:c.79+2T>AMANE SELECT
  • LRG_510t1:c.79+2T>A
  • LRG_510:g.5126T>A
  • NC_000001.10:g.43803600T>A
  • NM_005373.2:c.79+2T>A
  • c.79+2T>A (p.?)
Links:
dbSNP: rs146249964
NCBI 1000 Genomes Browser:
rs146249964
Molecular consequence:
  • NM_005373.3:c.79+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
MPL-related disorder
Synonyms:
MPL-Related Disorders; MPL-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000914405Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)		Likely pathogenic
(Dec 14, 2018) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004115979PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 20, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A founder mutation in the MPL gene causes congenital amegakaryocytic thrombocytopenia (CAMT) in the Ashkenazi Jewish population.

Jalas C, Anderson SL, Laufer T, Martimucci K, Bulanov A, Xie X, Ekstein J, Rubin BY.

Blood Cells Mol Dis. 2011 Jun 15;47(1):79-83. doi: 10.1016/j.bcmd.2011.03.006. Epub 2011 Apr 13.

PubMed [citation]
PMID:
21489838

MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: the type of mutation predicts the course of the disease.

Germeshausen M, Ballmaier M, Welte K.

Hum Mutat. 2006 Mar;27(3):296.

PubMed [citation]
PMID:
16470591
See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914405.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The MPL c.79+2T>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.79+2T>A variant was identified in a homozygous state in two individuals with congenital amegakaryocytic thrombocytopenia (CAMT) and in a heterozygous state in the unaffected parents of one of the individuals (Germeshausen et al. 2006; Jalas et al. 2011). The variant has not been reported in the literature in association with autosomal dominant essential thrombocythemia. The c.79+2T>A variant was absent from 50 control individuals but is reported at a frequency of 0.00057 in the European (non-Finnish) population from the Exome Aggregation Consortium. In a study of 2018 randomly selected individuals of Ashkenazi Jewish descent, Jalas et al. (2011) established a carrier frequency for the c.79+2T>A variant of one in 75. Haplotype analysis in this study suggested that the c.79+2T>A variant is a founder variant that is part of a haplotype with two upstream variants, though presence of these upstream variants cannot be assessed by the current test. Based on the evidence and the potential impact of splice donor variants, the c.79+2T>A variant is classified as likely pathogenic for MPL-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From PreventionGenetics, part of Exact Sciences, SCV004115979.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The MPL c.79+2T>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in patients with autosomal recessive congenital amegakaryocytic thrombocytopenia (Germeshausen et al. 2006. PubMed ID: 16470591; Jalas et al. 2011. PubMed ID: 21489838). The c.79+2T>A variant has also been characterized as a founder variant in the Ashkenazi Jewish population, being reported in 0.82% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (Jalas et al. 2011. PubMed ID: 21489838). However, it does not occur frequently in other gnomAD populations. Variants that disrupt the consensus splice donor site in MPL are expected to be pathogenic. This variant is interpreted as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024