Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004595572 | SCV001244326 | likely pathogenic | Hereditary thrombocytopenia and hematologic cancer predisposition syndrome | 2024-06-24 | reviewed by expert panel | curation | The NM_001754.4:c.596G>A (p.Gly199Glu) variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 26884589, 25159113, 24732596; internal laboratory data). The variant was found to co-segregate with disease in multiple affected family members, with three meioses observed across 2 families (PP1; PMID: 26884589, 25159113, 24732596; internal laboratory data). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It affects one of the non-hot-spot residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.956) (PP3). 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: PM2_supporting, PS4_Moderate, PP1, PP3, PM1_Supporting. |
| Labcorp Genetics |
RCV001078217 | SCV001544669 | likely pathogenic | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2022-05-27 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RUNX1 function (PMID: 24732596). 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 missense change has been observed in individuals with thrombocytopenia (PMID: 24732596, 25159113, 32208489). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 199 of the RUNX1 protein (p.Gly199Glu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 869210). |