Submissions for variant NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg)

gnomAD frequency: 0.00006  dbSNP: rs749004431

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV002264703	SCV002546386	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2021-06-22	reviewed by expert panel	curation	The NM_001754.5(RUNX1):c.649G>A (p.Gly217Arg) variant is reported in gnomAD v3.1 at an MAF of 0.0001064 (0.01%, 7/65790 alleles) in the non-Finish European subpopulation, which does not meet the thresholds for BA1 (≥0.0015) or BS1 (0.00015-0.0015). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PMID: 29365323); however, PS4 cannot be applied as 9 alleles overall are noted in gnomAD. This missense variant has a REVEL score of 0.624, which does not meet the threshold for PP3 (>0.75) or BP4 (<0.15). 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: none.
Genetic Services Laboratory, University of Chicago	RCV000501810	SCV000596878	uncertain significance	not specified	2017-02-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694237	SCV000822672	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-09-15	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. ClinVar contains an entry for this variant (Variation ID: 436614). This variant is also known as Gly190Arg. This missense change has been observed in individual(s) with familial platelet disorder with B-cell precursor acute lymphoblastic leukemia and/or hereditary hematopoietic malignancies (PMID: 20880108, 29365323). This variant is present in population databases (rs749004431, gnomAD 0.008%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 217 of the RUNX1 protein (p.Gly217Arg).
Fulgent Genetics, Fulgent Genetics	RCV000765505	SCV000896808	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1; Acute myeloid leukemia	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV002473028	SCV002770245	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with various hematologic malignancies (PMID: 24098673, 29365323, 33850299); Published functional studies demonstrate association with a cellular growth advantage (PMID: 24098673); This variant is associated with the following publications: (PMID: 20880108, 24098673, 29365323, 33850299, Nitschke2023[article], 28277065)
Baylor Genetics	RCV003470632	SCV004209829	uncertain significance	Acute myeloid leukemia	2023-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004965510	SCV005495275	uncertain significance	Inborn genetic diseases	2024-10-17	criteria provided, single submitter	clinical testing	The p.G217R variant (also known as c.649G>A), located in coding exon 6 of the RUNX1 gene, results from a G to A substitution at nucleotide position 649. The glycine at codon 217 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in an individual with features consistent with RUNX1 familial platelet disorder with associated myeloid malignancies (Drazer MW et al. Blood Adv, 2018 Jan;2:146-150). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.