F9 p.Ala337Pro

The c.1009G>C (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by proline at amino acid 337 (p.Ala337Pro). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant has been previously reported in at least one patient with mild hemophilia B (PMID: 1998585), meeting phenotypic criteria for F9. An additional proband with severe hemophilia B has been reported in the EAHAD Factor IX (F9) variant database. The computational predictor REVEL gives a score of 0.617, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). Different missense variants causing a change at the same residue (p.Ala337Thr and p.Ala337Val) have been established as pathogenic for F9 and SpliceAI predicts no impact on splicing meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Moderate + PM2_Supporting + PP3 + PM5. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023).