Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001001419 | SCV001158654 | pathogenic | not specified | 2019-05-06 | criteria provided, single submitter | clinical testing | The F9 c.127C>T; p.Arg43Trp variant, also known as p.Arg-4Trp, is reported in the literature in numerous individuals affected with moderate to severe hemophilia B (Chavali 2009, Green 1992, Knobloch 1993, Li 2014, Factor IX database and references therein). Additional variants at the same codon (p.Arg43Gln, p.Arg43Leu) have been reported in individuals with hemophilia B and are considered pathogenic (Chavali 2009, Green 1992, Knobloch 1993, Li 2014, Factor IX database). The arginine at codon 43 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that the p.Arg43Trp variant is deleterious. In assays of clotting activity, the p.Arg43Trp, p.Arg43Gln, and p.Arg43Leu variants generally exhibit less than 5% of wildtype activity, consistent with moderate to severe hemophilia (Chavali 2009, Green 1992, Factor IX database). The p.Arg43Trp variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Factor IX database: http://www.factorix.org Chavali S et al. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009 Dec;94(6):433-7. Green PM et al. Haplotype analysis of identical factor IX mutants using PCR. Thromb Haemost. 1992 Jan 23;67(1):66-9. Knobloch O et al. Recurrent mutations in the factor IX gene: founder effect or repeat de novo events. Investigation of the German haemophilia B population and review of de novo mutations. Hum Genet. 1993 Aug;92(1):40-8. Li T et al. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol. 2014 Apr;89(4):375-9. |
| Labcorp Genetics |
RCV001860507 | SCV002227189 | pathogenic | Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect | 2022-12-29 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Arg43 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1615486, 19699296, 22639855). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt F9 protein function. ClinVar contains an entry for this variant (Variation ID: 811505). This variant is also known as 6364C>T and Arg4Trp. This missense change has been observed in individuals with hemophilia B (PMID: 1615486, 19699296, 22639855). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 43 of the F9 protein (p.Arg43Trp). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001815019 | SCV003934297 | pathogenic | Hereditary factor IX deficiency disease | 2023-05-02 | criteria provided, single submitter | clinical testing | Variant summary: F9 c.127C>T (p.Arg43Trp) results in a non-conservative amino acid change located in the Gamma-carboxyglutamic acid-rich (GLA) domain (IPR000294) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181989 control chromosomes (gnomAD). c.127C>T has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (example: Green_1992 and Hamasaki-Katagiri_2012). This variant is also known as 6364C>T and Arg4Trp. Functional analysis have shown this variant results in <10% clotting activity (example: Chavali_2009). The following publications have been ascertained in the context of this evaluation (PMID: 1615486, 22639855, 19699296). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV001815019 | SCV000031538 | pathogenic | Hereditary factor IX deficiency disease | 1992-01-23 | no assertion criteria provided | literature only |