ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.611G>A (p.Arg204Gln) (rs1569061762)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV001078214 SCV001244323 pathogenic Familial platelet disorder with associated myeloid malignancy 2019-08-18 reviewed by expert panel curation The NM_001754.4:c.611G>A (p.Arg204Gln) variant affects one of the 13 hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.958) (PP3). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ moderate; PMID: 19357396, PMID: 27112265, PMID: 26316320, PMID: 27479822). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed across 3 families (PP1_strong; PMID: 19357396, PMID: 27112265, PMID: 26316320, PMID: 27479822). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_strong, PM1, PM2, PS4_moderate, PP3.
PreventionGenetics,PreventionGenetics RCV000680427 SCV000807798 pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing
Invitae RCV001078214 SCV001491515 uncertain significance Familial platelet disorder with associated myeloid malignancy 2020-03-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 204 of the RUNX1 protein (p.Arg204Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial platelet disorder with associated myeloid malignancy (PMID: 27112265, 19357396). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg177Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 561253). This variant has been reported to affect RUNX1 protein function (PMID: 11830488, 10068652, 22012064). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000680427 SCV001748021 pathogenic not provided 2021-05-01 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003538 SCV001161866 likely pathogenic Thrombocytopenia no assertion criteria provided research
Birmingham Platelet Group; University of Birmingham RCV001270615 SCV001450914 likely pathogenic Abnormal bleeding; Thrombocytopenia 2020-05-01 no assertion criteria provided research

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