Submissions for variant NM_005373.3(MPL):c.378del (p.Phe126fs)

dbSNP: rs587778515

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255711	SCV000321907	pathogenic	not provided	2025-05-02	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11133753, 36451132, 28859041, 29625052, 33258288, 35972311, 37647632, 38496821, 16470591, 33712866, 30996850)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780430	SCV000917676	pathogenic	Congenital amegakaryocytic thrombocytopenia	2018-06-22	criteria provided, single submitter	clinical testing	Variant summary: MPL c.378delT (p.Phe126LeufsX5) 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. The variant allele was found at a frequency of 4e-05 in 277158 control chromosomes. The variant, c.378delT, has been reported in the literature in multiple individuals affected with Congenital Amegakaryocytic Thrombocytopenia (Ballmaier_2001, Germeshausen_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000780430	SCV001162890	pathogenic	Congenital amegakaryocytic thrombocytopenia		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047546	SCV001211511	pathogenic	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2024-11-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe126Leufs*5) 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 (rs587778515, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 16470591, 28859041). ClinVar contains an entry for this variant (Variation ID: 265249). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000255711	SCV002017528	pathogenic	not provided	2020-01-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016657	SCV005651136	pathogenic	Primary myelofibrosis; Thrombocythemia 2; Congenital amegakaryocytic thrombocytopenia 1	2024-04-29	criteria provided, single submitter	clinical testing
ITMI	RCV000121537	SCV000085731	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000780430	SCV001453974	pathogenic	Congenital amegakaryocytic thrombocytopenia	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734911	SCV005356649	pathogenic	MPL-related disorder	2024-05-20	no assertion criteria provided	clinical testing	The MPL c.378delT variant is predicted to result in a frameshift and premature protein termination (p.Phe126Leufs*5). This variant has been reported in the homozygous or compound heterozygous states in multiple individuals with amegakaryocytic thrombocytopenia (Ballmaier et al. 2001. PubMed ID: 11133753; Lo et al. 2018. PubMed ID: 28859041; Germeshausen et al. 2006. PubMed ID: 16470591). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MPL are expected to be pathogenic. This variant is interpreted as pathogenic.