Submissions for variant NM_001754.5(RUNX1):c.978C>A (p.Asp326Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV005001415	SCV005627422	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2025-01-15	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.978C>A (p.Asp326Glu) is a missense variant which has a REVEL score < 0.50 (0.075), and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003630134	SCV004395893	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-02-03	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 326 of the RUNX1 protein (p.Asp326Glu).