ClinVar Miner

Submissions for variant NM_005373.3(MPL):c.391+5G>C

gnomAD frequency: 0.00012  dbSNP: rs752453717
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414099 SCV000490615 pathogenic not provided 2022-08-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect resulting in inefficient splicing and diminished protein expression (Gandhi et al, 2005); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 26369627, 19388932, 22102270, 11972523, 32703794, 31589614, 33572923, 16219544)
Laboratory for Molecular Medicine, Mass General Brigham 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 thrombocythemia 2024-01-25 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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs752453717, gnomAD 0.02%). This variant has been observed in individual(s) with atypical presentation of congenital amegakaryocytic thrombocytopenia (PMID: 16219544). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372409). Studies have shown that this variant alters MPL gene expression (PMID: 16219544). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000414099 SCV002067317 likely pathogenic not provided 2019-12-12 criteria provided, single submitter clinical testing DNA sequence analysis of the PARN gene demonstrated a sequence change located near the canonical splice donor site in intron 3, c.391+5G>C. This sequence change has been previously described in three siblings with late presentation of congenital amegakaryocytic thrombocytopenia in a biallelic state with a frameshift pathogenic variant (PMID: 16219544). In vitro functional studies have shown that this variant leads to inefficient splicing at exon 3 and has an impact on MPL expression and function compared to the wildtype MPL. This sequence change has been described in the gnomAD database with a low population frequency of 0.023% in non-Finnish subpopulation (dbSNP rs752453717). The presence of this sequence change together with the truncating variant described above is suggestive of this variant being likely pathogenic.
Revvity Omics, Revvity RCV000414099 SCV003819608 pathogenic not provided 2022-07-01 criteria provided, single submitter clinical testing

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