Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004595486 | SCV000965616 | pathogenic | Hereditary thrombocytopenia and hematologic cancer predisposition syndrome | 2024-03-26 | reviewed by expert panel | curation | Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.328A>G (p.Lys110Glu) variant and data from secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 23848403; 17290219; 11830488). This variant was found to co-segregate with disease in multiple affected family members, with 7 meioses observed in one pedigree (PP1_Strong; PMID: 11830488). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.953) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). This variant is a missense change at the same residue (p.K110) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 1518631, 14465) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PP1_Strong, PM1, PM2_supporting, PP3, PS4_Supporting, PM5_supporting. |
| Prevention |
RCV000680403 | SCV000807774 | pathogenic | not provided | 2014-01-03 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000015551 | SCV004297384 | pathogenic | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2023-11-13 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 110 of the RUNX1 protein (p.Lys110Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with leukemia (PMID: 1958483, 11830488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14465). 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 RUNX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 11830488). This variant disrupts the p.Lys110 amino acid residue in RUNX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10068652, 19448675, 21725049, 29055018). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000015551 | SCV000035816 | pathogenic | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2002-02-15 | no assertion criteria provided | literature only |