Submissions for variant NM_001754.5(RUNX1):c.1242C>G (p.Tyr414Ter)

dbSNP: rs2056452818

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV002264820	SCV002546429	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2022-04-25	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.1242C>G (p.Tyr414Ter) is a nonsense variant predicted to not undergo NMD (PVS1_strong 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: 33560381, Supplemental Table 3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PS4_supporting.
GeneDx	RCV001557333	SCV001779081	likely pathogenic	not provided	2020-08-10	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation as the last 67 amino acids are lost, and one loss-of-function variant has been reported downstream in the Human Gene Mutation Database (Sorrell 2012); Not observed in large population cohorts (Lek 2016); Observed in individuals with personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and segregates with disease in affected individuals from a single family in published literature (Chisholm 2019); This variant is associated with the following publications: (PMID: 30600763, 32208489)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003629190	SCV004375145	likely pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-06-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr414*) in the RUNX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acid(s) of the RUNX1 protein. This premature translational stop signal has been observed in individual(s) with clinical features of familial platelet disorder with associated myeloid malignancy (PMID: 30600763). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the inhibitory domain and the VWRPY domain of the RUNX1 protein, which are important for regulating RUNX1 protein stability and function (PMID: 22689681, 23753029, 15749889, 14504086). While functional studies have not been performed to directly test the effect of this variant on RUNX1 protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 1194557).