Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV002249971 | SCV002519692 | likely pathogenic | Thrombophilia, X-linked, due to factor 9 defect | 2024-06-25 | criteria provided, single submitter | clinical testing | The p.(Arg449Trp) variant in F9 has been previously reported in the medical literature and in the F9 Mutation Database in at least 10 patients with mild Hemophilia B (F9 Variant Database - UCL (https://www.factorix.org/advance_search_results.php?dosearch=1&codon=449 ; https://pubmed.ncbi.nlm.nih.gov/8076946/ ; https://pubmed.ncbi.nlm.nih.gov/31272859/). Functional analysis in HepG2 Cells disclosed moderate reductions in both intracellular and secreted factor IX levels for this mutant (https://pubmed.ncbi.nlm.nih.gov/9100030/). This variant has a MAF of 0.00005976, with 19 homozygous males in population databases (gnomAD v4.0.1 non-UKB), which is not higher than expected for a pathogenic mild Hemophilia B variant. Moreover, another missense mutation at this residue (p.Arg449Trp) has been previously identified in multiple patients with Hemophilia B. Therefore, we interpret p.(Arg449Gln) as likely pathogenic. |
| Victorian Clinical Genetics Services, |
RCV002471265 | SCV002767955 | uncertain significance | Hereditary factor IX deficiency disease | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Hemophilia B (MIM#306900). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (3 heterozygotes, 0 homozygotes, 6 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (7 heterozygotes, 0 homozygotes, 2 hemizygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change (GS = 43). (SB) 0600 - Variant is located in the annotated trypsin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. The missense variant p.(Arg449Trp) has previously been reported in multiple mild hemophilia B patients however the arginine to tryptophan substitution constitutes a much larger physicochemical change (GS: 101) than the change to glutamine. Therefore, this could not be used as supporting evidence for the p.(Arg449Gln) variant. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in patients diagnosed with mild hemophilia B (PMIDs: 31272859, 29517974, Factor IX Variant Database) however has also been reported as likely benign (LOVD). In addition, this variant was also reported as a polymorphism in the Factor IX database's main publication (PMID:23617593, Factor IX Variant Database). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Labcorp Genetics |
RCV003094026 | SCV003466923 | uncertain significance | Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect | 2022-05-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 449 of the F9 protein (p.Arg449Gln). This variant is present in population databases (rs143018900, gnomAD 0.03%). This missense change has been observed in individuals with mild hemophilia B (PMID: 7937052, 8091381, 10739381, 19699296, 22639855). This variant is also known as R403Q. 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 not expected to disrupt F9 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155471 | SCV003844836 | uncertain significance | not specified | 2024-01-23 | criteria provided, single submitter | clinical testing | Variant summary: F9 c.1346G>A (p.Arg449Gln) results in a conservative amino acid change located in the serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 182856 control chromosomes (gnomAD), including 7 hemizygotes. This frequency is not significantly higher than estimated for a pathogenic variant in F9 causing Factor IX Deficiency (Hemophilia B) (8.2e-05 vs 0.0065), allowing no strong conclusion about variant significance. c.1346G>A has been reported in the literature in individuals with a mild phenotype in the Hemophilia B database and other study cohorts (e.g. Giannelli_1994, Chavali_2009, Hamasaki_2012, Carrette_2019, Baz_2021, Johnsen_2022). These reports do not provide unequivocal conclusions about association of the variant with Factor IX Deficiency (Hemophilia B). 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: 34272389, 7937052, 22639855, 35770352, 8091381, 19699296, 31272859). ClinVar contains an entry for this variant (Variation ID: 1685804). Based on the evidence outlined above, the variant was classified as uncertain significance. |