Submissions for variant NM_005373.3(MPL):c.127C>T (p.Arg43Ter)

gnomAD frequency: 0.00004  dbSNP: rs148434485

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411190	SCV000487190	pathogenic	Congenital amegakaryocytic thrombocytopenia	2016-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778238	SCV000914406	pathogenic	MPL-related disorder	2018-10-04	criteria provided, single submitter	clinical testing	The MPL c.127C>T (p.Arg43Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant has been reported in three studies in which it is identified in a total of six individuals with congenital amegakaryocytic thrombocytopenia, all with a severe phenotype, in one individual in a compound heterozygous state and in five individuals in a homozygous state (Ballmaier et al. 2001; Germeshausen et al. 2006; Savoia et al. 2007). The p.Arg43Ter variant has not been reported in individuals with essential thrombocythemia. The p.Arg43Ter variant was absent from 50 controls and is reported at a frequency of 0.000041 in the total population of the Exome Aggregation Consortium. Savoia et al. (2007) demonstrated that platelet surface expression of other glycoproteins was normal in one individual carrying the variant but MPL expression was scarcely detectable. Serum TPO levels were elevated and in colony-forming unit assays, platelet c-MPL and bone marrow colonies were reduced. Based on the evidence and potential impact of stop-gained variants, the p.Arg43Ter variant is classified as pathogenic for MPL-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001248333	SCV001421808	pathogenic	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg43*) in the MPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). This variant is present in population databases (rs148434485, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 16470591). ClinVar contains an entry for this variant (Variation ID: 371574). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411190	SCV002015069	pathogenic	Congenital amegakaryocytic thrombocytopenia	2021-10-25	criteria provided, single submitter	clinical testing	Variant summary: MPL c.127C>T (p.Arg43X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251424 control chromosomes. c.127C>T has been reported in the literature in multiple individuals affected with Congenital Amegakaryocytic Thrombocytopenia (example, Ballmaier_2001, Germeshausen_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001782878	SCV002017531	pathogenic	not provided	2021-09-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001782878	SCV004700125	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MPL: PVS1, PM2, PM3
Natera, Inc.	RCV000411190	SCV002086019	pathogenic	Congenital amegakaryocytic thrombocytopenia	2021-08-25	no assertion criteria provided	clinical testing