Submissions for variant NM_000133.4(F9):c.572G>A (p.Arg191His)

gnomAD frequency: 0.00001  dbSNP: rs137852238

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV000011331	SCV004363686	pathogenic	Hereditary factor IX deficiency disease	2024-02-09	reviewed by expert panel	curation	The NM_000133.3(F9):c.572G>A predicts a missense change, Arg191His, at the activation residue. This residue is a site for cleavage by FXIa in order to activate FIX and therefore critical for protein function, which meets criteria for PM1_Strong. Over 100 patients meet the F9 phenotype criteria have been reported in the literature (selected PMIDs: 7873393,1972560, 26782891, 27865967, 24375831), meeting PS4_Very strong and PP4_Moderate. The variant has a REVEL score of 0.73 (threshold >0.6), meeting PP3. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: PS4_Very Strong, PM1_Strong, PP4_Moderate, PP3.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851602	SCV000899353	pathogenic	Hereditary factor VIII deficiency disease	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390296	SCV001591979	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2023-09-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg191 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: 10585). This variant is also known as p.Arg145His. This missense change has been observed in individuals with hemophilia B (PMID: 1615486, 2752109, 2773937, 19699296, 22544209, 22639855). This variant is present in population databases (rs137852238, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 191 of the F9 protein (p.Arg191His).
Mendelics	RCV002247326	SCV002519687	pathogenic	Thrombophilia, X-linked, due to factor 9 defect	2022-05-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002284168	SCV002573771	pathogenic	not provided	2021-06-18	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate, PM1, PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011331	SCV004020464	pathogenic	Hereditary factor IX deficiency disease	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: F9 c.572G>A (p.Arg191His) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 183455 control chromosomes. c.572G>A has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (Example: (Green_1992, Li_2014). These data indicate that the variant is very likely to be associated with disease. In addition, another missense variant in the same residue (p.Arg191Cys) has been classified as pathogenic in our laboratory, supporting the functional importance of this residue of the protein. 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: 1615486, 24375831). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000011331	SCV000031562	pathogenic	Hereditary factor IX deficiency disease	1990-11-15	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000011331	SCV001161882	pathogenic	Hereditary factor IX deficiency disease		no assertion criteria provided	research
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV000011331	SCV001424894	pathogenic	Hereditary factor IX deficiency disease	2019-06-01	no assertion criteria provided	clinical testing