Submissions for variant NM_001754.5(RUNX1):c.586A>G (p.Thr196Ala)

dbSNP: rs2057541324

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV002264771	SCV002546456	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2022-06-30	reviewed by expert panel	curation	The NM_001754.4: c.586A>G (p.Thr196Ala) variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (AA T196) (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It. This missense variant has a REVEL score >0.88(0.957) (PP3). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ Moderate; PMID: 27479822, SCV001450794.1, PMID: 31698193). This variant is a missense change at the same residue (p.Thr196) where a different missense change has been previously reported as a pathogenic variant (PMID: 34233450, p.(Thr196Ile), p.(Thr196Arg)) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects. PM5 cannot be applied at this stage as these variants still need to be recognized as pathogenic by MM-VCEP. In summary, this variant meets criteria to be classified as a Likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP3, PM2_supporting, PS4_Supporting
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002280903	SCV002569220	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1		criteria provided, single submitter	clinical testing
Birmingham Platelet Group; University of Birmingham	RCV001270495	SCV001450794	likely pathogenic	Abnormal bleeding; Thrombocytopenia	2020-05-01	no assertion criteria provided	research