Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003387953 | SCV005437144 | likely pathogenic | Hereditary factor IX deficiency disease | 2024-11-05 | reviewed by expert panel | curation | The NM_000133.4(F9):c.520G>A (p.Val174Met) missense variant is completely absent from gnomAD v2.1.1 and v3.1.2 meeting criteria for PM2_Supporting. The variant has a REVEL score of 0.811 (>0.6) meeting criteria for PP3. The variant changes the last nucleotide of exon 5 and SpliceAI predicts a donor loss of intron 5 (delta score of 0.66) meeting criteria for PM1. At least four probands with moderate or severe hemophilia B are reported in the literature and internal laboratory data (PMID: 1680287; doi: 10.5336/medsci.2020-75066), meeting criteria for PS4. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 (Released 10/5/2023): PM1, PS4_Moderate, PP3, PM2_Supporting. |
| ARUP Laboratories, |
RCV001001431 | SCV001158667 | likely pathogenic | not specified | 2019-07-01 | criteria provided, single submitter | clinical testing | The F9 c.520G>A; p.Val174Met variant, also published as Val128Met in mature protein nomenclature, is reported in the medical literature in at least two individuals with hemophilia B (Chavali 2009, Giannelli 1994). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant in the same codon, p.Val174Leu, has been reported in an individual with hemophilia B (wang 2016). The valine at this position is highly conserved, occurs in the linker domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant also occurs in the last nucleotide of the exon, which is often a conserved G nucleotide, and splicing algorithms (Alamut v.2.11) predict this variant disrupts the canonical splice donor, which may negatively impact gene function. Considering available information, this variant is classified as likely pathogenic. References: Chavali S et al. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009 Dec;94(6):433-7. 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. Wang QY et al. A genetic analysis of 23 Chinese patients with hemophilia B. Sci Rep. 2016 Apr 25;6:25024. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003387953 | SCV004099625 | likely pathogenic | Hereditary factor IX deficiency disease | 2023-09-08 | criteria provided, single submitter | clinical testing | Variant summary: F9 c.520G>A (p.Val174Met) results in a 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant results in skipping of exon 5 (Balestra_2019). The variant was absent in 178517 control chromosomes. c.520G>A has been reported in the literature in individuals affected with Factor IX Deficiency (Hemophilia B)(Bottema_1991, Giannelli_1994). The following publications have been ascertained in the context of this evaluation (PMID: 1680287, 7937052, 31234407, 27109384, 19699296). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |