Submissions for variant NM_001754.5(RUNX1):c.592G>T (p.Asp198Tyr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV003448648	SCV004176253	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2023-12-09	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.592G>T (p.Asp198Tyr) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant affects one of the 13 hotspot residues established by the MM-VCEP for RUNX1 (PM1). This missense variant has a REVEL score ≥ 0.88 (0.964) (PP3). Yeast assays showed significant decreased DNA binding, CBFbeta binding and promoter activation indicating that this variant impacts protein function (PMIDs 17290219, 23848403)(PS3_Supporting). This variant has been reported in 3 probands of a family meeting RUNX-1 phenotypic criteria (FPD and/or AML) (PMID 11675361) (PS4_supporting, PP1_supporting). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PP1_supporting, PP3, PM2_supporting, PS3_supporting, PS4_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005100107	SCV005839289	likely pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 198 of the RUNX1 protein (p.Asp198Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial platelet disorder with associated myeloid malignancy (PMID: 11675361). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2665098). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 23848403). This variant disrupts the p.Asp198 amino acid residue in RUNX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12393679, 18192504, 19850737, 23471304). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV005220716	SCV005870226	pathogenic	not provided	2024-08-12	criteria provided, single submitter	clinical testing	Identified in the germline of individuals with a personal and family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (PMID: 37738626, 11675361); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35802949, 17290219, 23848403, Guijarro2024[case Report], Christopeit2017[Poster], 29348313, 11675361, 37738626)