PB1136 - Improving Genetic Testing for Antithrombin Deficiency by Optimizing ACMG/AMP Variant Curation Guidelines for the SERPINC1 Gene

Tuesday, June 27, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Kristy Lee, MS, CGC

Genetic counselor
Department of Genetics, University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States

Co-Author(s)

SM

Shruthi Mohan

Staff scientist
Department of Genetics, University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
ST

Sean Tracey

Staff scientist
Versiti Medical Sciences Institute
Milwaukee, Wisconsin, United States
JM

Joel Morales-Rosado

Pathology resident
Department of Pathology, Microbiology and Immunology, Vanderbilt University
Nashville, Tennessee, United States
BB

Brian Branchford

Pediatric Hematologist-Oncologist
Versiti Medical Sciences Institute
Wauwatosa, Wisconsin, United States
Elisabetta Castoldi, PhD

Associate Professor
Department of Biochemistry, CARIM, Maastricht University, Maastricht (The Netherlands)
Maastricht, Limburg, Netherlands
Ang Li, MD, MS

Assistant Professor
Section of Hematology-Oncology, Baylor College of Medicine
Houston, Texas, United States
Christelle Orlando, PhD

Clinical lab expert
Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of laboratory haematology, Laarbeeklaan 101, 1090 Brussels, Belgium.
Brussels, Brussels Hoofdstedelijk Gewest, Belgium
AP

Amanda B. Payne

Epidemiologist
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention
Atlanta, Georgia, United States
VT

Valerie Trapp-Stamborski

Director, Hematology Genetics
Versiti Diagnostic Laboratory
Milwaukee, Wisconsin, United States
MF

Margaret Fergusson

Coordinator
Department of Genetics, University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
David-Alexandre TREGOUET, PhD (he/him/his)

Senior Investigator
Bordeaux Population Health research center - INSERM UMR1219
Bordeaux, Aquitaine, France
PM

Pierre-Emmanuel Morange, MD, PhD

MD, PhD
Aix-Marseille Univ, INSERM, INRAE, C2VN, Laboratory of Haematology, Hôpitaux de Marseille, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France

Background: Genetic testing for antithrombin deficiency can be beneficial for patients with indeterminate antithrombin levels and diagnosis of thrombophilia in patients on anticoagulation therapies. Improving variant curation guidelines for the SERPINC1 gene should limit the number of variants of uncertain significance (VUS) and decrease the number of discrepant variant interpretations between laboratories.

Aims: The Clinical Genome Resource (ClinGen), funded by the National Human Genome Research Institute, convened the Thrombosis Variant Curation Expert Panel (VCEP) in January 2020 to write rule specifications for curating variants in the SERPINC1 gene through their FDA-approved process. The 2015 American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) variant curation framework was used to specify rule codes for SERPINC1.

Methods: Each ACMG/AMP rule code was assessed for its appropriateness for antithrombin deficiency and whether there would be any benefit to adding detailed criteria for its use and/or modifying its strength (very strong, strong, moderate or supporting). A pilot study was then undertaken to test the rule specifications for 52 SERPINC1 variants previously classified as pathogenic, benign or VUS by ClinVar and/or expert VCEP members.

Results: Variant curation specifications were applied to 18 ACMG/AMP rule criteria and 9 rule codes were deemed not applicable to SERPINC1. Most variants (71.2%) in the pilot study resulted in the same classifications as reported in ClinVar or by VCEP members; however, 9.6% moved to in a benign/likely benign or pathogenic/likely pathogenic classification from a VUS classification and 17.3% of variants resulted in a VUS classification from a benign/likely benign or pathogenic/likely pathogenic classification (see Figure 1). One variant reported in the ClinVar database as benign moved to a pathogenic classification.

Conclusion(s): Results of this effort will help standardize variant curations for antithrombin deficiency across laboratories, as all curation work will be deposited in the ClinVar database for public access.