Submissions for variant NM_000133.4(F9):c.1150C>T (p.Arg384Ter)

gnomAD frequency: 0.00001  dbSNP: rs137852261

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000158	SCV001156644	pathogenic	not specified	2019-06-14	criteria provided, single submitter	clinical testing	The F9 c.1150C>T; p.Arg384Ter variant (rs137852261) is reported in the literature in multiple individuals affected with moderate to severe hemophilia B (Chen 1991, Giannelli 1994, Factor IX database and references therein). Functional assays indicate that patients with this variant exhibit clotting activity less than 1% of wildtype (Chen 1991, Giannelli 1994). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the F9 gene, which may not lead to nonsense-mediated decay but is expected to truncate the final 78 amino acids. Additionally, truncating variants downstream of p.Arg384Ter have been reported in individuals with hemophilia B and are considered disease-causing (Giannelli 1994). Based on available information, the p.Arg384Ter variant is considered to be pathogenic. References: Factor IX database: http://www.factorix.org Chen SH et al. CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series. Hum Genet. 1991 Jun;87(2):177-82. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048961	SCV001212991	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg384*) in the F9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the F9 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hemophilia B (PMID: 2066105, 2741941, 18624698, 22544209). This variant is also known as Arg338Stop. ClinVar contains an entry for this variant (Variation ID: 10615). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398481	SCV004120115	pathogenic	F9-related disorder	2023-01-06	criteria provided, single submitter	clinical testing	The F9 c.1150C>T variant is predicted to result in premature protein termination (p.Arg384*). This variant, previously described as p.Arg338*, has been reported to be causative for Hemophilia B (Chen et al. 1991. PubMed ID: 2066105; Huang et al. 2020. PubMed ID: 32875744; Villarreal-Martínez et al. 2020. PubMed ID: 32224444). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in F9 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000011361	SCV000031593	pathogenic	Hereditary factor IX deficiency disease	1989-07-01	no assertion criteria provided	literature only
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV000011361	SCV001424903	pathogenic	Hereditary factor IX deficiency disease	2019-06-01	no assertion criteria provided	clinical testing