PB0219 - Utility of ACMG classification to support interpretation of molecular genetic test results in patients with FVII deficiency

Background: An internationally shared framework for variant classification in genetic disorders has been established by the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG–AMP). However, there is a lack of data on the utility of ACMG classification for the interpretatio in patients with rare bleeding disorders.

Aims: To understand better the utility of ACMG classification in patients with FVII deficiency

Methods: Records of patients (pts) with FVII deficiency from the Coagulation Center Hochtaunus/ Mannheim, Germany where retrospectively reviewed. Ttreatment for substitution was documented. The cohort was divided into five groups according to genotype and pathogenicity of F7 gene variants: (1) wildtype, (2) ACMG 1 (benign) or ACMG 2 (likely benign), (3) ACMG 3 (uncertain significance), (4) single heterozygous ACMG 4 (likely pathogenic) or ACMG 5 (pathogenic) ± single heterozygous ACMG 1–3, (5) homozygous ACMG 4–5 or ≥ 2 heterozygous ACMG 4–5.

Results: In total, 111 pts. (74 females, 37 males, median age 32.5 years) with FVII deficiency (mean FVII:C 41.2 % ± 15.5 %) were included. F7 gene variants were detected in 89 pts.: 13 ACMG 1/2 variants (c.1238G>A in 68 pts.), 10 ACMG 3 variants , and 28 ACMG 4 or 5 variants (c.1061C>T in 18 pts.). Mean FVII:C in group 5 was 29.5 ± 13.6 % versus 48.6 ± 14.0 % in group 1, 45.7 ± 14.5 % in group 2, 44.1 ± 11.0 % in group 3, and 43.4 ± 13.6 % in group 4.

Conclusion(s): ACMG classification is a promising tool to improve interpretation of genetic test results in pts. with FVII deficiency. Our analysis suggest phenotype differences between pts. with a homogenous ACMG 4–5 F7 gene variant and pts. with F7 gene wildtype. This may serve as a basis to develop a genotype/phenotype prediction model in future.