ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414099 SCV000490615 pathogenic not provided 2020-10-21 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: inefficient splicing and diminished protein expression (Gandhi et al, 2005); This variant is associated with the following publications: (PMID: 26369627, 19388932, 22102270, 16219544, 11972523, 32703794, 31589614)
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,; 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 2020-07-07 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.

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