Submissions for variant NM_000133.4(F9):c.1345C>T (p.Arg449Trp)

gnomAD frequency: 0.00009  dbSNP: rs757996262

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851683	SCV000899483	likely pathogenic	Hereditary factor VIII deficiency disease	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811478	SCV001472104	pathogenic	not provided	2019-08-22	criteria provided, single submitter	clinical testing	The F9 c.1345C>T; p.Arg449Trp variant (rs757996262) is reported in the literature in multiple individuals affected with mild hemophilia B (Giannelli 1994, Factor IX database and references therein). Clotting assays performed on patient samples with this variant exhibit between 19% and 40% normal clotting activity (Factor IX database and references therein). This variant is found on only eight chromosomes (8/204623 alleles) in the Genome Aggregation Database. The arginine at codon 449 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, another amino acid substitution at this codon (p.Arg449Gln) has also been reported in individuals with hemophilia B and is considered disease-causing (Giannelli 1994, Factor IX database and references therein). Based on available information, the p.Arg449Trp variant is considered to be pathogenic. References: Factor IX database: http://f9-db.eahad.org/ Giannelli F et al. Haemophilia B: database of point mutations and short additions and deletions, fifth edition, 1994. Nucleic Acids Res. 1994 Sep;22(17):3534-46.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001655593	SCV001870325	uncertain significance	Hereditary factor IX deficiency disease	2020-05-15	criteria provided, single submitter	research	ACMG codes:PP5
Mendelics	RCV002249470	SCV002519691	pathogenic	Thrombophilia, X-linked, due to factor 9 defect	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002533972	SCV003034669	likely pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 449 of the F9 protein (p.Arg449Trp). This variant is present in population databases (rs757996262, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of F9-related conditions (PMID: 7937052, 8680410, 19699296, 22639855). This variant is also known as 31328C>T (Arg403Trp). ClinVar contains an entry for this variant (Variation ID: 626990). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on F9 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230584	SCV003928799	uncertain significance	not specified	2023-04-16	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV004753031	SCV005345527	uncertain significance	F9-related disorder	2024-04-10	no assertion criteria provided	clinical testing	The F9 c.1345C>T variant is predicted to result in the amino acid substitution p.Arg449Trp. This variant (also described as "C31328T" and "Arg403Trp" using legacy nomenclature) has been reported to cause mild to very mild hemophilia B (~13-41% clotting activity) in multiple individuals (Montejo et al. 1999. PubMed ID: 10094553; Jenkins et al. 2008. PubMed ID: 18479429; Chavali et al. 2009. PubMed ID: 19699296; Johnsen et al. 2022. PubMed ID: 35770352). However, this variant has also been reported in 8 out of ~204,600 alleles in the gnomAD v2 database (as displayed in the table above), including 4 hemizygous individuals. In addition, in gnomAD v4 (available only on GRCh38), this variant is reported in 176 out of ~1,209,000 alleles, including 61 hemizygotes. This population data is not consistent with this variant being a primary cause of disease. While this variant may be causative, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.