ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.523C>G (p.Leu175Val)

gnomAD frequency: 0.00001  dbSNP: rs868726626
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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 RCV004734328 SCV005367765 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-09-25 reviewed by expert panel curation NM_001754.5(RUNX1):c.523C>G (p.Leu175Val) is a missense variant which has been found in one individual from gnomAD v2.1.1 (MAF: 0.000003976). This variant is located within the Runt Homology Domain (AA 89-204), but does not occur 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: PM1_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001901442 SCV002175065 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-05-21 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 175 of the RUNX1 protein (p.Leu175Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 1404038). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function. 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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