ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.601dup (p.Arg201fs)

dbSNP: rs2146234527
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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 RCV003448405 SCV004176265 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-12-09 reviewed by expert panel curation NM_001754.5(RUNX1):c.601dup (p.Arg201ProfsTer12) is a frameshift variant. The transcript product is predicted to undergo NMD (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has been reported in 1 proband with family history meeting RUNX-1 phenotypic criteria (thrombocytopenia) (PMID 26175287) (PS4_supporting). This variant was also reported in Clinvar in 2021 by Invitae but the affected status of the proband is unknown (Variation ID 1073884). There are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) without use of PM5_Supporting (PMID: 35764482) (PM5_supporting). In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_supporting, PM2_supporting, PM5_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001387019 SCV001587507 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2020-10-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with thrombocytopenia (PMID: 26175287). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg201Profs*12) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448).

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