Submissions for variant NM_000133.4(F9):c.853G>T (p.Glu285Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469944	SCV002765919	likely pathogenic	Hereditary factor IX deficiency disease	2022-11-15	criteria provided, single submitter	clinical testing	Variant summary: F9 c.853G>T (p.Glu285X) results in a premature termination codon in the last exon of the F9 gene, predicted to cause a truncation of the encoded protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 178394 control chromosomes (gnomAD). c.853G>T has been reported in the literature in at least one individual affected with Factor IX Deficiency (Hemophilia B) (Li_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003775502	SCV004571524	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2024-07-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu285*) in the F9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 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: 24375831; Invitae). ClinVar contains an entry for this variant (Variation ID: 1804647). This variant disrupts a region of the F9 protein in which other variant(s) (p.Arg294*) have been determined to be pathogenic (PMID: 2270538, 8217825, 8314564, 10595634, 22544209, 23093250, 24375831, 26612714). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.