ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.400G>C (p.Ala134Pro)

dbSNP: rs74315451
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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 RCV004595488 SCV000965618 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-03-26 reviewed by expert panel curation Transactivation assays demonstrate altered transactivation (<20% of wt) for the missense variant, NM_001754.4:c.400G>C (p.Ala134Pro) and data from secondary assays demonstrate altered CBFβ binding and sub-cellular localization.(PS3; PMID: 23848403). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has a REVEL score >0.75 (0.945) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 12060124). It was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 12060124). This variant is a missense change at the same residue (p.A134) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 1484777) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). 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, PM2_supporting, PP1, PP3, PS4_Supporting, PM5_Supporting.
OMIM RCV000015554 SCV000035819 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2002-06-01 no assertion criteria provided literature only

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