ClinVar Miner

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

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Total submissions: 4
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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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270105 SCV001448936 pathogenic Inherited bleeding disorder, platelet-type 2019-10-04 criteria provided, single submitter clinical testing
Invitae RCV000477937 SCV001575463 likely pathogenic Familial platelet disorder with associated myeloid malignancy 2020-05-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 166 of the RUNX1 protein (p.Arg166Gln). The arginine residue is moderately 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 thrombocytopenia, myelodysplastic syndrome and/or acute myeloid leukemia (PMID: 28960434, 27210295, 26175287, 10508512). It has also been observed to segregate with disease in related individuals. This variant is also known as c.416G>A, p.Arg139Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 417961). This variant has been reported to affect RUNX1 protein function (PMID: 11830488, 25840971, 26916619, 31048839, 22012064, 23848403). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
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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