Submissions for variant NM_000133.4(F9):c.277+5G>A

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994820	SCV004813238	likely pathogenic	Hereditary factor IX deficiency disease	2024-02-08	criteria provided, single submitter	clinical testing	Variant summary: F9 c.277+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 181450 control chromosomes (gnomAD database v4.0.0). c.277+5G>A has been reported in the literature in individuals affected with Factor IX Deficiency (Hemophilia B)(Giannelli_1996, Wulff_1999, Balraj_2012). Additionally, other variants at the same site (c.277+5G>C, c.277+5G>T) have been reported in the literture in individuals with Factor IX Deficiency. 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. The following publications have been ascertained in the context of this evaluation (PMID: 22870602, 8594556, 10698280). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.