Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002025904 | SCV002289974 | pathogenic | Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 154 of the MPL protein (p.Trp154Arg). This variant is present in population databases (rs758428763, gnomAD 0.007%). This missense change has been observed in individuals with congenital amegakaryocytic thrombocytopenia (PMID: 16470591, 18090929, 26316487). ClinVar contains an entry for this variant (Variation ID: 1504060). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MPL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MPL function (PMID: 20188141, 24438083). For these reasons, this variant has been classified as Pathogenic. |
Fulgent Genetics, |
RCV002486650 | SCV002798088 | likely pathogenic | Congenital amegakaryocytic thrombocytopenia; Primary myelofibrosis; Thrombocythemia 2 | 2022-04-26 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV004538731 | SCV004113907 | likely pathogenic | MPL-related disorder | 2023-02-07 | criteria provided, single submitter | clinical testing | The MPL c.460T>C variant is predicted to result in the amino acid substitution p.Trp154Arg. This variant in the homozygous condition was reported in at least three individuals with amegakaryocytic thrombocytopaenia, congenital (Germeshausen et al 2006. PubMed ID: 16470591; Ok Bozkaya İ et al 2015. PubMed ID: 26316487; Table 1, Steinberg et al 2007. PubMed ID: 18090929; Germeshausen. 2021. PubMed ID: 32703794). Functional studies suggest that p.Trp154Arg variant led to abnormal protein expression (Fox et al 2010. PubMed ID: 20188141). In ClinVar, this variant is interpreted as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/1504060/?new_evidence=true). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-43805010-T-C). This variant is interpreted as likely pathogenic. |