ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.464T>C (p.Val155Ala)

gnomAD frequency: 0.00001  dbSNP: rs750866158
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV004774591 SCV005382703 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-10-29 reviewed by expert panel curation NM_001754.5(RUNX1):c.464T>C (p.Val155Ala) is a missense variant which has a REVEL score ≥ 0.88 (0.942) (PP3). This variant affects one of the residues within the Runt Homology Domain (AA 89-204) but not in an established hotspot residue (PM1_Supporting). 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: PP3, PM1_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001986366 SCV002281760 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-04-23 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 155 of the RUNX1 protein (p.Val155Ala). This variant is present in population databases (rs750866158, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1491218). 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%. 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.

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