Submissions for variant NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter)

gnomAD frequency: 0.00001  dbSNP: rs759068561

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV002264833	SCV002546444	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2022-04-25	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter) is a nonsense variant that is predicted to undergo NMD (PVS1, SNV Tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27210295). In summary, this variant meets the 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, PS4_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001949655	SCV002243317	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg166*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with features of RUNX1-related conditions (PMID: 21725049, 26525156, 28659335). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R139X. ClinVar contains an entry for this variant (Variation ID: 1459069). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002243494	SCV002512905	pathogenic	not provided	2022-04-25	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several individuals with familial platelet disorder/acute myeloid leukemia, and found to segregate with disease in multiple affected individuals from several families as well as occur de novo with confirmed parentage in patients tested at GeneDx and in published literature (Haslam 2016, Latger-Cannard 2016, Kanagal-Shamanna 2017); Published functional studies demonstrate defective hematopoiesis (Bluteau 2011, Bluteau 2012); Not observed in large population cohorts (gnomAD); Also known as p.Arg139Ter; This variant is associated with the following publications: (PMID: 26525156, 27112265, 28659335, 21725049, 22898599, 31124578, 33351114, 32315381)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001949655	SCV002515705	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1		no assertion criteria provided	research