Submissions for variant NM_000133.4(F9):c.224G>A (p.Arg75Gln)

gnomAD frequency: 0.00001  dbSNP: rs137852228

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV000011319	SCV005437139	pathogenic	Hereditary factor IX deficiency disease	2024-10-11	reviewed by expert panel	curation	NM_000133.4(F9):c.224G>A (p.Arg75Gln) missense variant has a REVEL score of 0.904, which meets criteria for PP3. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). Approximately 24 patients are reported in the literature with mild hemophilia B and this variant, meeting F9 phenotype criteria for PS4_Very strong (PMID: 31064749, PMID: 2066105, PMID: 8314564, PMID: 29296726, PMID: 27213901, PMID: 2773937). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PP4_Moderate, PP3, PM2_supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757260	SCV000885410	likely pathogenic	not provided	2018-04-17	criteria provided, single submitter	clinical testing	The F9 c.224G>A; p.Arg75Gln variant (rs137852228) has been described in several individuals with mild hemophilia B (see link to Factor IX database and references therein). It is reported in ClinVar (Variation ID: 10573) and is observed at a low overall frequency of 0.0006% (1/178366 alleles) in the Genome Aggregation Database. The arginine at codon 75 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. Additionally, other variants at this position (p.Arg75Gly, p. Arg75Pro) have been observed in individuals affected with hemophilia B and are considered pathogenic (see link to Factor IX database and references therein, Martensson 2016). Based on available information, this variant is considered likely pathogenic. References: Link to Factor IX database: http://www.factorix.org/ Martensson A et al. Mutation analysis of Swedish haemophilia B families - high frequency of unique mutations. Haemophilia. 2016 May;22(3):440-5.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852079	SCV000899604	pathogenic	Hereditary factor VIII deficiency disease	2019-02-01	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000011319	SCV001810420	likely pathogenic	Hereditary factor IX deficiency disease	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851790	SCV002149300	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2023-08-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 10573). This variant is also known as Arg29Gln. This missense change has been observed in individuals with hemophilia B (PMID: 2066105, 2773937, 19699296, 22639855, 24375831). This variant is present in population databases (rs137852228, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 75 of the F9 protein (p.Arg75Gln).
Fulgent Genetics, Fulgent Genetics	RCV002490353	SCV002813876	likely pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect; Warfarin sensitivity, X-linked	2022-01-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011319	SCV004223345	pathogenic	Hereditary factor IX deficiency disease	2023-11-01	criteria provided, single submitter	clinical testing	Variant summary: F9 c.224G>A (p.Arg75Gln) results in a conservative amino acid change located in the Gamma-carboxyglutamic acid-rich (GLA) domain (IPR000294) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182973 control chromosomes (gnomAD). c.224G>A has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (Chavali_2009, Hamasaki-Katagiri_2012, Meireles_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19699296, 22639855, 28722788). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000757260	SCV005413441	likely pathogenic	not provided	2024-05-29	criteria provided, single submitter	clinical testing	PP3, PM1_supporting, PM2_moderate, PS4_moderate
OMIM	RCV000011319	SCV000031550	pathogenic	Hereditary factor IX deficiency disease	1989-09-01	no assertion criteria provided	literature only