ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.713_726del (p.Val238fs)

dbSNP: rs2146075609
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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 RCV003405628 SCV004123224 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-11-13 reviewed by expert panel curation The c.713_726del (p.Val238Alafs*18) variant in RUNX1 is a frameshift deletion predicted to cause a premature stop codon in biologically-relevant exon 7/9 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent from gnomAD v2 and v3 with a mean coverage of at least 20X (PM2_Supporting). Although the variant has not been described in patients, there are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) with sufficient molecular and specific clinical data (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_Supporting, and PM5_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001380693 SCV001578821 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2020-10-05 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 conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val238Alafs*18) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product.

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