Submissions for variant NM_000133.4(F9):c.1136G>A (p.Arg379Gln)

dbSNP: rs137852259

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851995	SCV000899436	pathogenic	Hereditary factor VIII deficiency disease	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000156	SCV001156642	pathogenic	not specified	2018-08-26	criteria provided, single submitter	clinical testing	The F9 c.1136G>A; p.Arg379Gln variant (rs137852259), also known as p.Arg333Gln or 31119G>A in traditional nomenclature, is reported in the literature in multiple individuals and families affected with moderate to severe hemophilia B (Chavali 2009, Hamasaki-Katagiri 2012, Lin 2018, Factor IX database and references therein). This variant is reported in ClinVar (Variation ID: 10613), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, other variants at this codon (p.Arg379Gly/Pro/Leu) have been reported in individuals with moderate to severe hemophilia B (Factor IX database and references therein). The arginine at codon 379 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on available information, this variant is considered to be pathogenic. References: Link to Factor IX database: http://www.factorix.org/ Chavali S et al. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009 Dec;94(6):433-7. Hamasaki-Katagiri N et al. Analysis of F9 point mutations and their correlation to severity of haemophilia B disease. Haemophilia. 2012 Nov;18(6):933-40. Lin XY et al. Establishing a comprehensive genetic diagnosis strategy for hemophilia B and its application in Chinese population. Int J Lab Hematol. 2018 Apr;40(2):215-228.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851792	SCV002137345	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2023-08-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg379 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19699296). 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 not expected to disrupt F9 protein function. ClinVar contains an entry for this variant (Variation ID: 10613). This variant is also known as p.Arg333Gln. This missense change has been observed in individuals with hemophilia B (PMID: 22639855). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 379 of the F9 protein (p.Arg379Gln).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011359	SCV002765920	pathogenic	Hereditary factor IX deficiency disease	2022-11-11	criteria provided, single submitter	clinical testing	Variant summary: F9 c.1136G>A (p.Arg379Gln) results in a conservative amino acid change located in the Trypsin-like serine protease domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function, while two tools predict the variant to be damaging or disease-causing. The variant was absent in 183173 control chromosomes. c.1136G>A has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (e.g. Hamasaki-Katagiri_2012, Yu_2012, Agrawal_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Jin_2004, Mathur_1999). The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000011359	SCV000031591	pathogenic	Hereditary factor IX deficiency disease	1988-10-01	no assertion criteria provided	literature only