Submissions for variant NC_000021.9:g.(?_34787801)_(34799462_?)del

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV000463520	SCV000965661	likely pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2019-08-07	reviewed by expert panel	curation	This deletion of exons 8+9 of RUNX1 affects critical protein domains (TAD, VWRPY-motif). Despite the unknown impact on the reading frame and no NMD-prediction, PVS1_Strong can be applied based on the impact on critical protein domains. In addition, the variant is absent from population databases (PM2) and 2 probands have been reported and met FPD/AML phenotype criteria (SCV000563938.2 and internal laboratories) (PS4_Moderate). 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, PS4_Moderate.
Invitae	RCV000463520	SCV000563938	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2016-11-21	criteria provided, single submitter	clinical testing	This variant is a gross deletion of the genomic region encompassing exons 8-9 of the RUNX1 gene. The 5' boundary is likely confined to intron 7. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. While a similar gross deletion has not been reported in the literature, loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). This variant is expected to result in the deletion of 212 amino acids of the RUNX1 protein (Asp269-Tyr480). While this is not anticipated to result in nonsense mediated decay, it is expected to result in the loss of the transcriptional activation domain (amino acid residues 318-398), DNA-binding inhibitory domain (residues 398-438), and VWRPY domain (residues 476-480) of the RUNX1 protein (PMID: 22689681, 23753029). Loss of these three domains from the mouse Runx1 protein has been shown to result in defects in thymocyte development (PMID: 15749889, 14504086). For these reasons, this variant has been classified as Pathogenic.