ClinVar

Description

Variant summary: F9 c.676C>T (p.Arg226Trp) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183448 control chromosomes (gnomAD). c.676C>T has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (examples: Ludwig_1992, Hamasaki-Katagiri_2012, Branchini_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Branchini_2021). Other variants affecting the same amino acid (e.g R226Q, R226G) has been reported in patients with severe form of Hemophila B (Hamasaki-Katagiri_2012, Branchini_2021 and HGMD). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.