ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.592G>T (p.Asp198Tyr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV003448648 SCV004176253 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-12-09 reviewed by expert panel curation NM_001754.5(RUNX1):c.592G>T (p.Asp198Tyr) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant affects one of the 13 hotspot residues established by the MM-VCEP for RUNX1 (PM1). This missense variant has a REVEL score ≥ 0.88 (0.964) (PP3). Yeast assays showed significant decreased DNA binding, CBFbeta binding and promoter activation indicating that this variant impacts protein function (PMIDs 17290219, 23848403)(PS3_Supporting). This variant has been reported in 3 probands of a family meeting RUNX-1 phenotypic criteria (FPD and/or AML) (PMID 11675361) (PS4_supporting, PP1_supporting). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP1_supporting, PP3, PM2_supporting, PS3_supporting, PS4_supporting.

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