Submissions for variant NM_000133.4(F9):c.1105C>T (p.Leu369Phe)

dbSNP: rs2148367939

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002023260	SCV002306522	likely pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2021-04-20	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu369 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19699296, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt F9 protein function. This variant has been observed in individual(s) with hemophilia B (PMID: 15921378). It is also known as p.Leu323Phe. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 369 of the F9 protein (p.Leu369Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155460	SCV003844834	uncertain significance	not specified	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: F9 c.1105C>T (p.Leu369Phe) 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 183203 control chromosomes (gnomAD). c.1105C>T has been reported in the literature in at least two individuals affected with Factor IX Deficiency (Hemophilia B) (e.g. Belvini_2005, Zhou_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.