ClinVar Miner

Submissions for variant NM_005373.2(MPL):c.391+5G>C (rs752453717)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414099 SCV000490615 pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing The c.391+5 G>C splice site variant in the MPL gene has been previously reported in association with CAMT (Gandhi et al, 2005). This variant reduces the quality of the splice donor site in intron 3, and is expected to cause abnormal gene splicing. The c.391+5 G>C substitution was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore we interpret this variant as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825643 SCV000967013 uncertain significance not specified 2018-01-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The c.391+5G>C variant in MPL has been reported in 3 members of 1 family with congenital amegak aryocytic thrombocytopenia (CAMT), all of whom carried a pathogenic variant on t he other MPL allele (Gandhi 2005). The c.391+5G>C variant has also been identifi ed in 27/126592 European chromsomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752453717). Although this variant has been seen in the general population, its frequency is low enough to be consisten t with a recessive carrier frequency. This variant is located in the 5' splice r egion. While in vitro functional studies suggest an impact to splicing (Gandhi 2 005), these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical sign ificance of the c.391+5G>C variant is uncertain. ACMG/AMP Criteria applied: PM2; PVS1_Supporting; PP1_Moderate.
Invitae RCV001042667 SCV001206364 pathogenic Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia 2019-05-24 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the MPL gene. It does not directly change the encoded amino acid sequence of the MPL protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs752453717, ExAC 0.03%). This variant has been observed to segregate with atypical presentation of congenital amegakaryocytic thrombocytopenia in a family (PMID: 16219544). ClinVar contains an entry for this variant (Variation ID: 372409). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16219544). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.