Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004595642 | SCV005088355 | likely pathogenic | Hereditary thrombocytopenia and hematologic cancer predisposition syndrome | 2024-06-24 | reviewed by expert panel | curation | NM_001754.5(RUNX1):c.401C>T (p.Ala134Val) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is a missense change at the same residue (p.Ala134) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 14468) based on MM-VCEP rules for RUNX1, and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5). This missense variant has a REVEL score ≥ 0.88 (0.949) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5, PP3, PM2_supporting. |
| Labcorp Genetics |
RCV002008165 | SCV002270958 | uncertain significance | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2022-10-17 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 134 of the RUNX1 protein (p.Ala134Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1484777). 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. 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. |