Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003153684 | SCV000629599 | uncertain significance | Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia | 2022-09-13 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Leu582Valfs*30) in the MPL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the MPL protein. This variant is present in population databases (rs770402221, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 458369). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MPL protein in which other variant(s) (p.Gly614Val) have been observed in individuals with MPL-related conditions (PMID: 17666371). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230532 | SCV003928218 | likely pathogenic | Congenital amegakaryocytic thrombocytopenia | 2023-04-05 | criteria provided, single submitter | clinical testing | Variant summary: MPL c.1744_1745delCT (p.Leu582ValfsX30) results in a premature termination codon, predicted to cause a truncation in the last exon of the encoded protein, which is a commonly known mechanism for disease. Although the variant is not expected to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acids of the protein. Downstream missense variants have been reported in the literature in individuals with congenital amegakaryocytic thrombocytopaenia (PMIDs: 18422784, 11071383, 17666371) and reported as pathogenic in ClinVar, suggesting the disrupted region is clinically significant. Additionally, truncating variants downstream of this position have been reported as pathogenic in ClinVar. The variant allele was found at a frequency of 1.6e-05 in 251472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1744_1745delCT in individuals affected with Congenital Amegakaryocytic Thrombocytopenia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |