Introduction 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). The EAHAD F7 variant database has been prepared
to list the pathogenicity of variants based on the ACMG classification. However, there
is a lack of data on the utility of ACMG classification for the interpretation of
molecular genetic test results in patients with FVII deficiency (1).
Method Records of patients (pts) with FVII deficiency examined at the Coagulation Center
Hochtaunus, Bad Homburg and Coagulation Center Mannheim, Germany, between 08/2012
and 12/2021 where retrospectively reviewed. Molecular genetic analyses were performed
at the Institute for Immunology/ Genetics, Kaiserslautern, Germany. The ISTH-SSC bleeding
assessment tool was used to generate a bleeding score (BS). Cut offs for an abnormal
ISTH-BS were ≥ 3 for children, ≥ 4 for males, ≥ 6 for females. In addition, treatment
for substitution of FVII deficiency 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), only, (3) ACMG 3 (uncertain significance),
only, or not classified, (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 or ≥ 1 heterozygous ACMG 4–5 plus either homozygous ACMG 1 c.1238G>A modifying
variant or ≥ 2 ACMG 1–3.
Results In total, 111 pts. (74 females, 37 males, median age 32.5 years, range 0–84 years)
with FVII deficiency (mean FVII:C 41.2 % ± 15.5 %) were included. F7 gene variants
were detected in 89 pts. (number of variants per patient: median 2, maximum 10) with
53 different variants listed: 13 ACMG 1 or 2 variants (c.1238G>A in 68 pts.), 10 ACMG
3 variants, 2 variants remained unclassified, 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. 11 of 31 pts. (35.5 %) in group 5, had abnormal ISTH-BS (n=7) and/or history of
on demand substitution with recombinant factor VIIa (n=5) versus 4 of 80 pts. (5.0
%, n=1 abnormal ISTH-BS, n=3 substitution) in groups 1 (n=2/22), 2 (n=1/29), 3 (n=0/9)
and 4 (n=1/20) [1]
[2].
Conclusion ACMG classification is a promising tool to improve interpretation of genetic test
results in pts. with FVII deficiency. The results of this retrospective analysis suggest
phenotype differences between pts. with a homogenous ACMG 4–5 F7 gene variant or specific
combinations of heterogenous ACMG 4–5 ± ACMG 1–3 variants, on one side, and pts. with
F7 gene wildtype, ACMG 1–3 variants, only, or single heterozygous ACMG 4–5 ± single
heterozygous ACMG 1–3 variant, on the other side. This may serve as a basis to develop
a genotype/phenotype prediction model in future studies (1,2).
