Abstract Number: PB0102
Meeting: ISTH 2021 Congress
Background: Genetic testing for hemophilia A/B aids in risk stratification and family planning and is a prerequisite for delivering precision medicine. As tailoring treatment will require knowledge of the disease-causing variant, limiting the number of variants of uncertain significance (VUS) and increasing the number of accurately curated variants in public databases will be critically important.
Aims: In 2015, the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) developed a framework to assess variant pathogenicity; however, the guidelines were written broadly. The Clinical Genome Resource (ClinGen), funded by the National Human Genome Research Institute, convened the Coagulation Factor Deficiency Variant Curation Expert Panel (CFD-VCEP) in December 2018 to develop rule specifications for curating variants in the F8/F9 genes through their FDA-approved process.
Methods: The CFD-VCEP membership meet monthly to specify ACMG-AMP rules for F8/F9 genes and discuss resulting variant assertions. Each rule was assessed for its appropriateness for hemophilia and whether there would be any benefit to adding detailed criteria for its use and/or modifying its strength based on availability of evidence.
Results: Variant curation specifications were applied to 19 ACMG-AMP rule criteria and 9 rules were deemed not applicable to these genes. Criteria modifications included setting allele frequencies in normal controls, defining key functional domains and residues and conditions for adjusting strength. A pilot study of 80 F9 and F8 variants, covering all bleeding severities, is currently underway to test the rule specifications. The goal is to curate 15 pathogenic/likely pathogenic, 10 VUS and 15 benign/likely benign variants for each gene. Rule specifications and variant classifications to be presented.
Conclusions: Results of this effort will aid clinical variant interpretation for the hemophilia genes and help standardize variant curations across laboratories. Expert level variant curation from this VCEP will be deposited in the ClinVar database for public access.
To cite this abstract in AMA style:Lee K, Chen X, Ding Q, Downes K, Doshi B, Ewen EP, Frantz A, McCreery J, Mohan S, Payne A, Tian X, Trapp-Stamborski V, Key NS, Konkle BA, Gomez K. Optimizing Variant Curation Guidelines to Improve Clinical Genetic Testing for Hemophilia A and B [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/optimizing-variant-curation-guidelines-to-improve-clinical-genetic-testing-for-hemophilia-a-and-b/. Accessed December 3, 2021.
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