ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.280A>C (p.Ser94Arg)

dbSNP: rs1057523598
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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 RCV003448309 SCV004176249 likely pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-09-10 reviewed by expert panel curation NM_001754.5(RUNX1):c.280A>C (p.Ser94Arg) is located within the RUNT homology domain but not within a mutational hotspot (PM1_supporting). Transactivation assays demonstrate reduced transactivation (<20% of wild-type) and data from a beta-heterodimerization assay demonstrate loss of beta-heterodimerization (PS3; unpublished data and PMID: 23817177). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; internal laboratory data, VCV000389962.2). This missense variant has a REVEL score ≥ 0.88 (0.947) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PS4_supporting, PM2_supporting, PP3, PM1_supporting.
GeneDx RCV000424160 SCV000532662 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing The S94R variant in the RUNX1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S94R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S94R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs within the Runt domain, at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S94R as a variant of uncertain significance.

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