Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001891969 | SCV002138784 | likely pathogenic | Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia | 2022-11-04 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Pro136 amino acid residue in MPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16470591, 24438083, 27100302, 32703794). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters MPL gene expression (PMID: 18422784). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1379348). This missense change has been observed in individual(s) with autosomal recessive congenital amegakaryocytic thrombocytopenia (PMID: 10971406, 32703794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs764904424, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 136 of the MPL protein (p.Pro136His). |