Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001810845 | SCV002050111 | pathogenic | not provided | 2020-12-16 | criteria provided, single submitter | clinical testing | The F9 c.301C>G; p.Pro101Ala variant (rs137852232), also known as p.Pro55Ala, is reported in the literature in multiple individuals affected with mild-to-moderate hemophilia B (see F9 database and references therein, Chavali 2009, Spitzer 1990). Functional analyses demonstrate that individuals with this variant have factor IX activity between 5-12% (F9 database, Chavali 2009). This variant is reported in ClinVar (Variation ID: 0578). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (p.Pro101Ser, p.Pro101Thr, p.Pro101Arg, p.Pro101Gln, p.Pro101Leu) have been reported in individuals with mild hemophilia B and are considered pathogenic (Green 1991, Miller 2012, Montejo 1999, Ketterling 1993). The proline at codon 101 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.936). Based on available information, the p.Pro101Ala variant is considered to be pathogenic. References: F9 Variant Database: https://f9-db.eahad.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. Haemophilia B mutations in a complete Swedish population sample: a test of new strategy for the genetic counselling of diseases with high mutational heterogeneity. Br J Haematol. 1991 Jul;78(3):390-7. Ketterling RP et al. Germ-line origins of mutation in families with hemophilia B: the sex ratio varies with the type of mutation. Am J Hum Genet. 1993 Jan;52(1):152-66. Miller CH et al. Hemophilia Inhibitor Research Study Investigators. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012 May;18(3):375-82. Spitzer SG et al. Factor IXHollywood: substitution of Pro55 by Ala in the first epidermal growth factor-like domain. Blood. 1990 Oct 15;76(8):1530-7. Montejo JM et al. Identification of twenty-one new mutations in the factor IX gene by SSCP analysis. Hum Mutat. 1999;13(2):160-5. |
| Labcorp Genetics |
RCV003764550 | SCV004571488 | pathogenic | Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect | 2023-12-24 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 101 of the F9 protein (p.Pro101Ala). This variant is present in population databases (rs137852232, gnomAD 0.02%). This missense change has been observed in individuals with hemophilia B (PMID: 2066105, 2743975, 19699296, 24375831). This variant is also known as 10415C>G (Pro55Ala). ClinVar contains an entry for this variant (Variation ID: 10578). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on F9 protein function. This variant disrupts the p.Pro101 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7937052; Invitae). 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. |
| OMIM | RCV000011324 | SCV000031555 | pathogenic | Hereditary factor IX deficiency disease | 1989-04-01 | no assertion criteria provided | literature only |