ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.509-?_613+?del

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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 RCV000240172 SCV000965663 likely pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2019-08-06 reviewed by expert panel curation This in-frame deletion of exon 6 of RUNX1 does disrupt the critical RUNT homology DNA-binding domain which affects a crucial functional domain (PVS1_Strong). In addition, this deletion is absent from population databases (PM2). One proband shows a typical FPD/AML phenotype (PS4_supporting) and there is evidence of segregation of the deletion with disease in affected family members (PP1). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_Strong, PM2, PP1, PS4_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000240172 SCV000299148 likely pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2016-04-27 criteria provided, single submitter clinical testing This variant is a gross deletion of the genomic region encompassing exon 6 of the RUNX1 gene. This leads to an in-frame deletion, preserving the integrity of the reading frame. This deletion is not present in population databases. A similar deletion of RUNX1 exon 6 has been reported in the literature in an individual affected with thrombocytopenia and leukemia (PMID: 19946261). A missense substitution within this exon (p.Arg201Gln) is reported to be deleterious (PMID: 10508512, 21725049). This indicates that the Arginine residue, and therefore exon 6, is important for RUNX1 protein function. In summary, this variant is an in-frame gross deletion of exon 6 that has been reported in an affected individual and it has been shown to be important for RUNX1 protein function. For these reasons, it has been classified as Likely Pathogenic.

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