Curating the Clinical Genome 2024 ePoster Gallery-Upcoming Changes to the Version 3 RUNX1 Curation Rules

Upcoming Changes to the Version 3 RUNX1 Curation Rules

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The document discusses the significance of RUNX1 gene mutations in familial platelet disorder with associated myeloid malignancies (FPD/AML) and the challenges they pose in patient care. The ClinVar database often categorizes these mutations as variants of uncertain significance (VUS), leading to difficulties in clinical classification. The Myeloid Malignancies Variant Curation Expert Panel (MM-VCEP) revised guidelines in 2021 to address these challenges. However, this resulted in an increase in VUS categorizations, indicating a need for more robust evidence for classification.<br /><br />To improve curation practices, the document introduces an R-based computational script for curation of single nucleotide variants (SNVs) in the RUNX1 gene. The script utilizes data from databases like ClinVar and gnomAD to simulate the impact of potential rule changes on variant classification, particularly focusing on VUS categorizations.<br /><br />The study suggests changes to the curation rules, such as incorporating more functional assay data, setting minimum thresholds for population codes, and refining classifications for DNA binding residues and splicing variants. These updates aim to reduce the number of VUS and better capture variants in critical regions of the gene.<br /><br />The authors plan to publish more functional assay data, establish a patient engagement program, and complete the curation of remaining variants. Future directions include re-curating old VUS and updating deposited curations to align with current rules. The document highlights key references and acknowledgments towards the efforts of the Myeloid Malignancy VCEP and biocurators involved in the research.

Keywords

RUNX1 gene mutations

familial platelet disorder

associated myeloid malignancies

variants of uncertain significance

Myeloid Malignancies Variant Curation Expert Panel

R-based computational script

single nucleotide variants

functional assay data

DNA binding residues

patient engagement program