Submissions for variant NM_001754.5(RUNX1):c.146del (p.Pro49fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004700889	SCV005205684	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-09-10	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.146del (p.Pro49GlnfsTer4) is a nonsense variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (nonsense c.917-c.1440 as per VCEP specifications) (PVS1_Strong). This variant has been reported in four or more probands meeting at least one of the RUNX1-phenotypic criteria (PS4). It is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is located downstream of c.98 (PM5_supporting). 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_Strong, PM2_supporting, PM5_supporting, PS4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003016883	SCV003319412	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2022-02-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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 sequence change creates a premature translational stop signal (p.Pro49Glnfs*4) 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).