ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.352-1G>T

dbSNP: rs587776809
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV000015549 SCV000965627 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2019-08-01 reviewed by expert panel curation The NM_001754.4:c.352-1G>T variant is a canonical splice site variant that is predicted to introduce a frameshift and a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1; PMID: 10508512). This variant was found to co-segregate with disease in multiple affected family members, with more than seven meioses (at least 25 affected individuals) observed in one family/across X families (PP1_Strong; 10508512). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 11830488). 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, PP1_Strong, PM2, PS4_Supporting.
PreventionGenetics, part of Exact Sciences RCV000680408 SCV000807779 pathogenic not provided 2016-03-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000015549 SCV003443975 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2022-04-21 criteria provided, single submitter clinical testing Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 10508512). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 14463). This sequence change affects an acceptor splice site in intron 4 of the RUNX1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with familial thrombocytopenia (PMID: 10508512). It has also been observed to segregate with disease in related individuals.
OMIM RCV000015549 SCV000035814 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 1999-10-01 no assertion criteria provided literature only

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