ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.489dup (p.Val164fs)

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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 RCV003408207 SCV004123215 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-11-13 reviewed by expert panel curation The c.489dup (p.Val164Cysfs*49) variant in RUNX1 is a frameshift duplication 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). It has also been described in a 67yo male with AML who had a daughter with AML at age 21 (HSCT at age 26), and an additional daughter and 2 sons with thrombocytopenia, but germline origin was not confirmed (PMID: 32804409, cited by PMID: 35884491) (PS4_Supporting does not apply). Regardless, 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.
GeneDx RCV002283276 SCV002571567 pathogenic not provided 2024-07-15 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with thrombocytopenia and/or myelodysplastic syndrome referred for genetic testing at GeneDx or in published literature and (PMID: 32804409); This variant is associated with the following publications: (PMID: 35884491, 32804409)

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