Submissions for variant NM_001754.5(RUNX1):c.610C>T (p.Arg204Ter)

dbSNP: rs1569061768

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV001374725	SCV001571654	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-03-26	reviewed by expert panel	curation	The c.610C>T (Arg204Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 5/8 and expected to result in nonsense-mediated mRNA decay (PVS1). It is completely absent from gnomAD v2.1.1 and v3 with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in three probands meeting at least one of the RUNX1- phenotypic criteria (PS4_Moderate; PMID: 32165484, 10508512, 26492932). It was also found to co-segregate with disease in multiple affected family members, with eight meioses observed in across 3 families (PP1_Strong; PMID: 10508512, 26492932 , 32165484). This variant is a nonsense/frameshift variants that is 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, PP1_strong, PS4_moderate, PM2_supporting, PM5_supporting.
PreventionGenetics, part of Exact Sciences	RCV000680426	SCV000807797	pathogenic	not provided	2014-01-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799444	SCV000939106	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-08-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 561252). This premature translational stop signal has been observed in individual(s) with familial platelet disorder with predisposition to acute myelogenous leukemia (PMID: 10508512). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg204*) 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).
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000799444	SCV002569219	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1		criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000799444	SCV001133125	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2019-09-26	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003539	SCV001161867	likely pathogenic	Thrombocytopenia		no assertion criteria provided	research