Submissions for variant NM_005373.3(MPL):c.79+2T>A (rs146249964)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254762	SCV000321905	pathogenic	not provided	2018-08-17	criteria provided, single submitter	clinical testing	The c.79+2 T>A variant in the MPL gene has been previously reported in the homozygous state in association with congenital amegakaryocytic thrombocytopenia (Germeshausen et al., 2006; Jalas et al., 2011). This pathogenic variant destroys the canonical splice donor site in intron 1, and is expected to cause abnormal gene splicing. The c.79+2 T>A variant is observed in 81/9910 (0.8%) alleles from individuals of Ashkenazi Jewish background in large population cohorts and has been reported as a founder mutation the Ashkenazi Jewish population (Lek et al., 2016; Jalas et al., 2011). We interpret c.79+2 T>A as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586535	SCV000698586	pathogenic	Congenital amegakaryocytic thrombocytopenia	2016-10-24	criteria provided, single submitter	clinical testing	Variant summary: The MPL c.79+2T>A variant involves the alteration of a splice donor site in intron 1, which 5/5 splice prediction tools predict the removal this splice donor site, however, functional studies have yet to be performed to assess these predictions. This variant was found in 58/100444 control chromosomes at a frequency of 0.0005774, which does not exceed the estimated maximal expected allele frequency of a pathogenic MPL variant (0.002357). This variant has been reported in two patients with Amegakaryocytic Thrombocytopenia in homozygous state (Germeshausen_2006 and Jalas_2011). It has also been reported as germline variant in patients with Breast Cancer, Non-Small Cell Lung Cancer, Melanoma and Non-Seminomatous Germ Cell Tumor (Schrader_2016). The variant is a founder mutation in Ashkenazi Jewish population with a carrier frequency of 1 in 75 (Jalas_2011). One clinical diagnostic laboratory in ClinVar classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000586535	SCV000712164	likely pathogenic	Congenital amegakaryocytic thrombocytopenia	2017-02-28	criteria provided, single submitter	clinical testing	The c.79+2T>A variant in MPL has been reported in the homozygous state in 2 indi viduals with congenital amegakaryocyctic thrombocytopenia (CAMT; Germeshausen 20 06, Jalas 2011). It has also been identified in 0.8% (80/9916) of Ashkenazi Jewi sh chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org/; dbSNP rs146249964), and is suggested to be a founder variant in th e Ashkenazi Jewish population (Jalas 2011). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause alt ered splicing leading to an abnormal or absent protein. Loss of function of the MPL gene is an established mechanism of disease. In summary, although additional studies are required to fully establish its clinical significance, the c.79+2T> A variant is likely pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000763338	SCV000894020	pathogenic	Congenital amegakaryocytic thrombocytopenia; Myelofibrosis; Thrombocytosis, benign familial microcytic	2018-10-31	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851882	SCV000899931	likely pathogenic	Thrombocytopenia	2019-02-01	criteria provided, single submitter	research
Illumina Clinical Services Laboratory,Illumina	RCV000778237	SCV000914405	likely pathogenic	MPL-Related Disorders	2018-12-14	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000801559	SCV000941339	likely pathogenic	Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia	2020-10-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 1 of the MPL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs146249964, ExAC 0.06%). This variant has been observed as homozygous in individuals affected with congenital amegakaryocytic thrombocytopenia and has been reported as a potential Ashkenazi Jewish founder mutation (PMID: 16470591, 21489838). ClinVar contains an entry for this variant (Variation ID: 135563). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000586535	SCV001162889	pathogenic	Congenital amegakaryocytic thrombocytopenia		criteria provided, single submitter	clinical testing
Myriad Women's Health, Inc.	RCV000586535	SCV001194134	pathogenic	Congenital amegakaryocytic thrombocytopenia	2019-12-20	criteria provided, single submitter	clinical testing	NM_005373.2(MPL):c.79+2T>A is classified as pathogenic in the context of congenital amegakaryocytic thrombocytopenia. Sources cited for classification include the following: PMID 21489838 and 16470591. Classification of NM_005373.2(MPL):c.79+2T>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV001330057	SCV001521650	pathogenic	Myelofibrosis	2019-05-23	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This c.79+2T>A variant has been previously reported as disease-causing in patients with CAMT (congenital amegakaryocytic thrombocytopenia) [PMID 16470591, 21489838]
ITMI	RCV000122423	SCV000083974	not provided	not specified	2013-09-19	no assertion provided	reference population
Reproductive Health Research and Development,BGI Genomics	RCV000586535	SCV001142298	pathogenic	Congenital amegakaryocytic thrombocytopenia	2020-01-06	no assertion criteria provided	curation	NG_007525.1(NM_005373.2):c.79+2T>A in the MPL gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is located on a biological transcript and leads to exon skipping or use of a cryptic splice site disrupts reading frame and is therefore predicted to undergo NMD. It has been reported as a founder mutation the Ashkenazi Jewish population (PMID: 21489838). This variant has been reported in homozygous state in two patients with Amegakaryocytic Thrombocytopenia (PMID: 16470591; 21489838). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PVS1; PM3; PP4
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000254762	SCV001554095	pathogenic	not provided		no assertion criteria provided	clinical testing	The MPL c.79+2T>A variant was identified in the literature as a homozygous variant in two unrelated patients with congenital amegakaryocytic thrombocytopenia (CAMT) (Germeshausen_2006_PMID:16470591; Jalas_2011_PMID:21489838). In a sample of 2018 individuals of Ashkenazi Jewish descent, the variant was found to have a carrier frequency of 1 in 75 (Jalas_2011_PMID:21489838). The variant was identified in dbSNP (ID: rs146249964) and ClinVar (classified as pathogenic by GeneDx, Integrated Genetics, Counsyl and Fulgent Genetics, and as likely pathogenic by Laboratory for Molecular Medicine, Invitae, Illumina and NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 97 of 259028 chromosomes at a frequency of 0.0003745 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 81 of 9646 chromosomes (freq: 0.008397), Other in 4 of 6556 chromosomes (freq: 0.00061) and European (non-Finnish) in 12 of 113480 chromosomes (freq: 0.000106), but was not observed in the African, Latino, East Asian, European (Finnish), or South Asian populations. The c.79+2T>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, four of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a difference in splicing and the loss of the canonical 5' splice site. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.