Submissions for variant NM_001754.5(RUNX1):c.484A>G (p.Arg162Gly)

dbSNP: rs1057519751

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV001290699	SCV001478836	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-03-26	reviewed by expert panel	curation	The c.484A>G variant in RUNX1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 162 (p.R162G), which is a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918), especially from a somatic perspective (PMID: 32208489) (PM1). This variant is absent from gnomAD v2 and v3 (PM2_Supporting), and has been reported in a proband meeting RUNX1-phenotypic criteria: history of bruising, menorrhagia, anemia, and a platelet defect with atypical platelet function tests, abnormal electron microscopy study, and atypical macrophages on bone marrow biopsy (PS4_Supporting; SCV001375396.1 and National Human Genome Research Institute). In addition, her older son (non-carrier) is unaffected, her younger son (carrier) has a history of thrombocytopenia (easy bleeding and bruising), frequent epistaxis, petechiae at 9 months, and an abnormal platelet electron microscopy study, and her mother (carrier) was diagnosed with AML at 45 (BMT done) and has a history of easy bleeding (PP1; National Human Genome Research Institute); finally, there is a supportive family history of AML in deceased relatives. Note that all other reports of the variant are not clearly germline (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). Functionally, the variant demonstrates reduced DNA-binding and CBFβ-binding (PMID: 17290219), as well as impaired erythropoiesis (PMID: 17234761, 21725049 (PS3_Moderate), which is in line with computational evidence (REVEL score of 0.885 ≥ 0.88 threshold; PP3). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3_Moderate, PS4_Supporting, PM1, PM2_Supporting, PP1, and PP3.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851801	SCV000899769	uncertain significance	Abnormal platelet function	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204199	SCV001375396	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2024-06-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 162 of the RUNX1 protein (p.Arg162Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RUNX1-related conditions (PMID: 31064749). This variant is also known as p.R135G. ClinVar contains an entry for this variant (Variation ID: 376022). 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 expected to disrupt RUNX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 12807882, 17234761, 24523240). 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.