Submissions for variant NM_000133.4(F9):c.1328T>C (p.Ile443Thr)

dbSNP: rs137852268

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810850	SCV001473253	pathogenic	not provided	2019-07-24	criteria provided, single submitter	clinical testing	The F9 c.1328T>C; p.Ile443Thr variant (rs137852268), also known as p.Ile397Thr or as the F9 Vancouver variant, is reported in the literature in numerous individuals and families affected with mild, moderate, or severe hemophilia B (Geddes 1989, Ketterling 1991, Li 2014, Thompson 1990, Factor IX database and references therein). This variant is one of the most common pathogenic variants in hemophilia B patients of European descent (Ketterling 1991), and individuals with this variant carry a shared haplotype, suggestive of a founder effect (Ketterling 1991, Thompson 1990). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Samples from affected individuals with this variant exhibit clotting activity at 12% or less of normal activity (Factor IX database and references therein). Additionally, enzymatic studies of p.Ile443Thr protein demonstrate substantially reduced catalytic efficiency (Geddes 1989). Based on available information, this variant is considered to be pathogenic. References: Factor IX database: http://www.factorix.org Geddes VA et al. A moderate form of hemophilia B is caused by a novel mutation in the protease domain of factor IXVancouver. J Biol Chem. 1989 Mar 15;264(8):4689-97. Ketterling RP et al. Evidence that descendants of three founders constitute about 25% of hemophilia B in the United States. Genomics. 1991 Aug;10(4):1093-6. Li T et al. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol. 2014 Apr;89(4):375-9. Thompson AR et al. "Founder" effect in different families with haemophilia B mutation. Lancet. 1990 Feb 17;335(8686):418.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382695	SCV001581597	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2023-09-17	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects F9 function (PMID: 2494175). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 443 of the F9 protein (p.Ile443Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophilia B (PMID: 2494175, 24375831). This variant is also known as p.Ile397Thr and "Factor IX Vancouver". ClinVar contains an entry for this variant (Variation ID: 10627). 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 not expected to disrupt F9 protein function. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001810850	SCV002573773	likely pathogenic	not provided	2021-09-17	criteria provided, single submitter	clinical testing	PP3, PP4, PP5, PM1, PM2, PS4_Moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011371	SCV004813249	pathogenic	Hereditary factor IX deficiency disease	2024-02-27	criteria provided, single submitter	clinical testing	Variant summary: F9 c.1328T>C (p.Ile443Thr) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR0012540) 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 182978 control chromosomes (gnomAD). c.1328T>C has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (example: Li_2014). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 24375831). ClinVar contains an entry for this variant (Variation ID: 10627). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000011371	SCV000031603	pathogenic	Hereditary factor IX deficiency disease	1991-06-01	no assertion criteria provided	literature only