ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.475A>G (p.Asn159Asp)

dbSNP: rs2057885323
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV004695233 SCV005196496 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-07-17 reviewed by expert panel curation NM_001754.5(RUNX1):c.475A>G (p.Asn159Asp) is a missense variant affecting one of the residues within the runt homology domain (AA 89-204) (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.88 (0.956) (PP3). Transactivation assays demonstrate normal transactivation at 80.43% (80-115% of wt), suggesting functional similarity to the wild type (BS3_Supporting; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, BS3_supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV001229885 SCV001402346 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-05-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 159 of the RUNX1 protein (p.Asn159Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glioma and/or acute lymphoblastic leukemia (PMID: 26580448, 34166225). ClinVar contains an entry for this variant (Variation ID: 956982). 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: 34166225). 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.
GeneDx RCV002462849 SCV002756700 uncertain significance not provided 2022-05-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with pediatric-onset B-cell acute lymphoblastic leukemia or low-grade glioma (Zhang et al., 2015; Li et al., 2021); This variant is associated with the following publications: (PMID: 34166225, 26580448)

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