Submissions for variant NM_000133.4(F9):c.*1157A>G

dbSNP: rs1317977313

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851959	SCV000899382	pathogenic	Hereditary factor VIII deficiency disease	2019-02-01	criteria provided, single submitter	research
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV003322818	SCV004028502	likely pathogenic	Hereditary factor IX deficiency disease	2023-07-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003322818	SCV004037789	pathogenic	Hereditary factor IX deficiency disease	2023-08-31	criteria provided, single submitter	clinical testing	Variant summary: F9 c.*1157A>G (also known as 32528A>G) is located in the untranslated mRNA region downstream of the termination codon. The variant was absent in 21563 control chromosomes (gnomAD). c.*1157A>G has been reported in the literature in multiple individuals affected with Factor IX Deficiency/Hemophilia B (e.g. Vielhaber_1993, Hinks_1999, Liu_2000, Bicocchi_2003, Downes_2019, Parrado Jara_2020). These data indicate that the variant is very likely to be associated with disease. Minigene assays have demonstrated that the variant creates a U1snRNP binding site, which recruits the U1snRNP complex. This suppresses the nearby poly(A) site from correctly processing the 3' end of the transcript, leading to RNA degradation (Krooss_2020). The following publications have been ascertained in the context of this evaluation (PMID: 12687663, 31064749, 10192459, 32267853, 10874302, 32155688, 8401514). Two ClinVar submitters have assessed the variant since 2014, one classified the variant as likely pathogenic and the other as pathogenic . Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003768318	SCV004571472	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2023-09-18	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the F9 gene. It does not change the encoded amino acid sequence of the F9 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individual(s) with hemophilia B (PMID: 8401514, 31064749, 32155688). In at least one individual the variant was observed to be de novo. This variant is also known as 32,528A>G or c.2545A>G. ClinVar contains an entry for this variant (Variation ID: 627188). Studies have shown that this variant alters F9 gene expression (PMID: 32267853). For these reasons, this variant has been classified as Pathogenic.