ClinVar Miner

Submissions for variant NM_005373.3(MPL):c.981-1G>C

gnomAD frequency: 0.00001  dbSNP: rs769297582
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000824356 SCV000965252 likely pathogenic Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia 2024-02-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the MPL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). This variant is present in population databases (rs769297582, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with endometrial cancer and/or ovarian cancer (PMID: 29625052, 30886832, 36451132). This variant is also known as g.43812115G>C. ClinVar contains an entry for this variant (Variation ID: 665962). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005004456 SCV002803677 likely pathogenic Primary myelofibrosis; Thrombocythemia 2; Congenital amegakaryocytic thrombocytopenia 1 2024-05-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001825676 SCV002819769 likely pathogenic Congenital amegakaryocytic thrombocytopenia 2024-05-07 criteria provided, single submitter clinical testing Variant summary: MPL c.981-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251340 control chromosomes. c.981-1G>C has been not been reported in the literature in individuals affected with Congenital Amegakaryocytic Thrombocytopenia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 665962). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV001825676 SCV002086030 likely pathogenic Congenital amegakaryocytic thrombocytopenia 2020-07-23 no assertion criteria provided clinical testing

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