ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.166_193dup (p.Ala65fs)

dbSNP: rs1569084530
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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 RCV001376068 SCV001573091 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-03-26 reviewed by expert panel curation The c.166_193dup (p.Ala65Valfs*82) variant is a 28-bp duplication causing a frameshift that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases (gnomAD v2.1.1 and v3) with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). The variant has not been reported in FPD/AML patients in the literature to the best of our knowledge; however one patient meeting RUNX1-phenotype criteria is reported from a clinical laboratory (PS4_Supporting; SCV000820350.2). 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: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000692523 SCV000820350 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2018-10-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). This variant has not been reported in the literature in individuals with RUNX1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala65Valfs*82) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product.

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