ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.872T>C (p.Ile291Thr)

gnomAD frequency: 0.00003  dbSNP: rs371026644
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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 RCV004692588 SCV005196438 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-08-12 reviewed by expert panel curation NM_001754.5(RUNX1):c.872T>C (p.Ile291Thr) is a missense variant which is reported at a MAF of 0.00007236 (0.007%, 3/41460 alleles) in the African/African American sub-population of the gnomAD v3.1.2 cohort and does not meet the threshold for BA1 (≥0.0015) or BS1 (0.00015 - 0.0015). The variant has a REVEL score of 0.228, which meets the threshold for BP4 (<0.50). 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 RCV001339101 SCV001532822 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-09-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 291 of the RUNX1 protein (p.Ile291Thr). This variant is present in population databases (rs371026644, gnomAD 0.008%). 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: 1036141). 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) indicates that this missense variant is not expected to disrupt RUNX1 protein function with a negative 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.
Baylor Genetics RCV004570812 SCV005055494 uncertain significance Acute myeloid leukemia 2023-12-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV004960811 SCV005495307 uncertain significance Inborn genetic diseases 2024-11-24 criteria provided, single submitter clinical testing The p.I291T variant (also known as c.872T>C), located in coding exon 7 of the RUNX1 gene, results from a T to C substitution at nucleotide position 872. The isoleucine at codon 291 is replaced by threonine, 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.

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