Submissions for variant NM_001754.5(RUNX1):c.411dup (p.Glu138Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004701773	SCV005205681	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-09-10	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.411dup (p.Glu138Ter) is a nonsense variant which is predicted to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). It is downstream of c.98 (PM5_Supporting) and impacts amino acid 138, which is located within the Runt Homology Domain (RHD) but does not occur in an established hotspot residue (PM1_Supporting). Clinical and functional data are not available for this variant. 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, PM2_Supporting, PM5_Supporting, PM1_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003630421	SCV004486268	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2022-12-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu138*) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448).