ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.484A>G (p.Arg162Gly) (rs1057519751)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV001290699 SCV001478836 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2021-01-12 reviewed by expert panel curation This missense variant has not been reported in gnomAD (v2 and v3) [PM2]. It has been reported as a germline variant in an unaffected proband (30s) who had a suggestive family history, including thrombocytopenia and AML (SCV001375396.1); however, all other reports of the variant are not clearly germline (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). The variant is located at 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]. The variant also demonstrates reduced DNA-binding and CBFβ-binding (PMID: 17290219), as well as impaired erythropoeisis (PMID: 17234761, 21725049) [PS3_moderate], which is in line with computational evidence [PP3]. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3_moderate, PM1, PM2, and PP3.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851801 SCV000899769 uncertain significance Abnormal platelet function 2019-02-01 criteria provided, single submitter research
Invitae RCV001204199 SCV001375396 uncertain significance Familial platelet disorder with associated myeloid malignancy 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 162 of the RUNX1 protein (p.Arg162Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 376022). This variant has been reported to affect RUNX1 protein function (PMID: 12807882, 17234761, 24523240). This variant is also known as p.R135G in the literature. 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.
Database of Curated Mutations (DoCM) RCV000434358 SCV000504775 likely pathogenic Acute myeloid leukemia 2014-10-02 no assertion criteria provided literature only

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