ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.497G>A (p.Arg166Gln) (rs1060499616)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV000477937 SCV000965620 pathogenic Familial platelet disorder with associated myeloid malignancy 2019-07-30 reviewed by expert panel curation Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.497G>A (p.Arg166Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBF-beta binding and sub-cellular localization (PS3; PMID: 11830488, 25840971, 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 10508512, 28960434, 26175287). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It has a REVEL score >0.75 (0.962) (PP3). There are two unrelated probands meeting at least one of the RUNX1- phenotypic criteria with assumed de novo occurrence (without confirmation of maternity and paternity) (PM6_ Supporting; PMID: 8960434, 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 10508512). 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, PM1, PS4_Moderate, PM2, PP3, PM6_Supporting, PP1.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477937 SCV000536928 likely pathogenic Familial platelet disorder with associated myeloid malignancy 2016-03-06 no assertion criteria provided research

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