Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV002249957 | SCV002519659 | pathogenic | Thrombophilia, X-linked, due to factor 8 defect | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003403750 | SCV004122664 | uncertain significance | not specified | 2023-10-10 | criteria provided, single submitter | clinical testing | Variant summary: F8 c.5144G>A (p.Arg1715Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 180241 control chromosomes, including 2 hemizygous males. c.5144G>A has been reported in the literature in individuals affected with Factor VIII Deficiency (Hemophilia A; e.g. Fernandez-Lopez_2005, Silva Pinto_2012). These data indicate that the variant may 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: 15921397, 21645180, 28748566). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| ARUP Laboratories, |
RCV003738163 | SCV004565201 | likely pathogenic | not provided | 2023-06-28 | criteria provided, single submitter | clinical testing | The F8 c.5144G>A; p.Arg1715Gln variant (rs781876217), also known as Arg1696Gln, is reported in the literature in individuals affected with mild hemophilia A (Fernandez-Lopez 2005, Markoff 2009, see link to F8 database and references therein). This variant is also reported in ClinVar (Variation ID: 1685790), and is found in the Latino/Admixed American population with an allele frequency of 0.015% (4/26827 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.850). Additionally, other variants at this codon (c.5143C>G; p.Arg1715Gly; c.5144G>C, p.Arg1715Pro) have been reported in individuals with mild or moderate hemophilia A (David 2006, Johnsen 2017, Markoff 2009, see link to F8 database). Based on available information, the p.Arg1715Gln variant is considered to be likely pathogenic. References: Link to F8 Database: https://f8-db.eahad.org/index.php David D et al. The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients. Haematologica. 2006 Jun;91(6):840-3. PMID: 16769589. Fernandez-Lopez O et al. The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations. Haematologica. 2005 May;90(5):707-10. PMID: 15921397. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. PMID: 29296726. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. PMID: 19473423. |
| Laboratory for Molecular Medicine, |
RCV004017909 | SCV004848900 | likely pathogenic | Hereditary factor VIII deficiency disease | 2023-02-02 | criteria provided, single submitter | clinical testing | The p.Arg1715Gln variant in F8 has been reported in 2 individuals with hemophilia (Fernández-López 2005 PMID: 15921397, Markoff 2009 PMID: 19473423), and was absent in large population databases. The variant has been reported in ClinVar (Variation ID 1685790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional variants involving this codon (p.Arg1715Gly, p.Arg1715Pro) have been identified in an individual with hemophilia (Reiner 1992 PMID: 1349567). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for X-linked recessive hemophilia. ACMG/AMP criteria applied: PM5, PS4_Supporting, PM2_Supporting, PP3, PP4. |