The NM_001754.4:c.205G>C variant that results in a Gly69Arg missense change has an MAF of 0.0003133 (0.03%, 6/19148 alleles) in the East Asian subpopulation of the gnomAD v2.1.1 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). Transactivation assays demonstrate normal transactivation as wild-type and normal DNA binding (BS3; PMIDs: 23817177 & 12393679). The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3.

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 69 of the RUNX1 protein (p.Gly69Arg). This variant is present in population databases (rs777168865, gnomAD 0.03%). This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 31470354). This variant is also known as c.124G>C (p.Gly42Arg). ClinVar contains an entry for this variant (Variation ID: 463990). 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. 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.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect (Harada et al., 2003; Koh et al., 2013); Observed in the germline of an individual with acute myeloid leukemia and no family history (Jeong et al., 2019); Also known as c.124C>G; p.G42R; This variant is associated with the following publications: (PMID: 35599145, 12393679, 23817177, 32956452, 31470354)

The p.G69R variant (also known as c.205G>C), located in coding exon 3 of the RUNX1 gene, results from a G to C substitution at nucleotide position 205. The glycine at codon 69 is replaced by arginine, an amino acid with dissimilar properties. One functional study reported that this variant maintained normal levels of transcriptional activity (Koh CP et al. Leukemia. 2013 Sep;27(9):1793-802). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.