Submissions for variant NM_005373.3(MPL):c.1565+5C>T

gnomAD frequency: 0.00488  dbSNP: rs41269541

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000122424	SCV000248071	benign	not specified	2021-06-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232182	SCV000288884	benign	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000282111	SCV000357784	likely benign	Thrombocythemia 1	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000337044	SCV000357785	likely benign	Congenital amegakaryocytic thrombocytopenia	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000337044	SCV000791933	uncertain significance	Congenital amegakaryocytic thrombocytopenia	2017-05-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001689671	SCV001909786	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122424	SCV002598813	benign	not specified	2022-09-16	criteria provided, single submitter	clinical testing	Variant summary: MPL c.1565+5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, however, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0046 in 279466 control chromosomes (gnomAD), predominantly at a frequency of 0.0073 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MPL causing Congenital Amegakaryocytic Thrombocytopenia (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1565+5C>T in individuals affected with Congenital Amegakaryocytic Thrombocytopenia and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014 without submitting evidence for clinical-significance assessments: one classified the variant as uncertain significance, one as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001689671	SCV004123654	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MPL: BP4, BS2
ITMI	RCV000122424	SCV000083975	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV004528839	SCV000311025	benign	MPL-related disorder	2020-10-12	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV000337044	SCV001453983	benign	Congenital amegakaryocytic thrombocytopenia	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001689671	SCV002034057	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001689671	SCV002035449	likely benign	not provided		no assertion criteria provided	clinical testing