ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.844_856del (p.Asp282fs)

dbSNP: rs2056577059
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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 RCV004695151 SCV005196564 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-08-01 reviewed by expert panel curation NM_001754.5(RUNX1):c.844_856del (p.Asp282fs) is a frameshift variant which is not predicted to result in nonsense-mediated mRNA decay but the truncated region is critical to protein function (PVS1_strong). This variant is downstream of c.98 (PM5_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has not been reported in individuals meeting the RUNX1 phenotypic criteria. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001202518 SCV001373631 likely pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2019-09-09 criteria provided, single submitter clinical testing 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. This variant disrupts the transcriptional activation domain (amino acid residues 318-398), DNA-binding inhibitory domain (residues 398-438), and VWRPY domain (residues 476-480) of the RUNX1 protein (PMID: 22689681, 23753029, 15749889, 14504086). This variant has not been reported in the literature in individuals with RUNX1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the RUNX1 gene (p.Asp282Asnfs*25). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 199 amino acids of the RUNX1 protein.

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