ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.1286T>G (p.Leu429Arg)

dbSNP: rs2056450952
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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 RCV004774533 SCV005382818 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-10-29 reviewed by expert panel curation NM_001754.5(RUNX1):c.1286T>G (p.Leu429Arg) is a missense variant which is absent from both gnomAD v2.1 and gnomAD v3.1.2 (PM2_supporting). This variant has not been reported in any proband meeting at least one of the RUNX1-phenotypic criteria. It has a REVEL score of 0.399, which is less than 0.50 (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001920749 SCV002186397 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-04-29 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 429 of the RUNX1 protein (p.Leu429Arg). This variant is not present in population databases (gnomAD no frequency). 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: 1411636). 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 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.

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