ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.899C>T (p.Thr300Met)

gnomAD frequency: 0.00001  dbSNP: rs758682659
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV003409633 SCV004123158 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2025-05-02 reviewed by expert panel curation NM_001754.5(RUNX1):c.899C>T (p.Thr300Met) is a missense variant which has a REVEL score < 0.50 (0.423) and a SpliceAI score of 0 (BP4). This variant has been observed in gnomAD v2.1 at a MAF of 0.00005274 (0.005274%, 6/113766) in the European (non-Finnish) sub-population, but does not meet any population criteria. It has not been reported in individuals with a RUNX1-defined phenotype. 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: BP4.
Labcorp Genetics (formerly Invitae), Labcorp RCV000461356 SCV000550152 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2025-01-20 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 300 of the RUNX1 protein (p.Thr300Met). This variant is present in population databases (rs758682659, gnomAD 0.005%). 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: 409809). Invitae Evidence 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 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.
Baylor Genetics RCV003470455 SCV004209850 uncertain significance Acute myeloid leukemia 2024-01-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV004965476 SCV005495294 uncertain significance Inborn genetic diseases 2024-11-28 criteria provided, single submitter clinical testing The p.T300M variant (also known as c.899C>T), located in coding exon 7 of the RUNX1 gene, results from a C to T substitution at nucleotide position 899. The threonine at codon 300 is replaced by methionine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx RCV005090912 SCV005848291 uncertain significance not provided 2024-08-16 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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