ClinVar

Description

Variant summary: F9 c.1345C>T (p.Arg449Trp) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 182873 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1345C>T has been reported in the literature as detected among cohorts of patients with Haemophilia B in the Haemophilia B database with some reports indicating it is non-causative/mild/not severe (example, Giannelli_1994, Wulff_1995, Montejo_1999, Jenkins_2008, Chavali_2009, Hamasaki-Katagiri_2012, Johnsen_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Factor IX Deficiency (Hemophilia B). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.