Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV003114183 | SCV003799963 | likely pathogenic | not provided | 2022-06-24 | criteria provided, single submitter | clinical testing | The F8 c.5143C>G; p.Arg1715Gly variant (rs137852439), also known as R1696G in traditional nomenclature, is reported in the literature in multiple individuals affected with mild hemophilia A (Jayandharan 2005, Johnsen 2017, Markoff 2009, see link to FVIII database). This variant is also reported in ClinVar (Variation ID: 10268), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1715 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.904). Additionally, other variants at this codon (c.5144G>A, p.Arg1715Gln; c.5144G>C, p.Arg1715Pro) have been reported in individuals with mild or moderate hemophilia A (David 2006, Markoff 2009). Based on available information, the p.Arg1715Gly variant is considered to be likely pathogenic. References: Link to FVIII 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. Jayandharan G et al. Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions. Haemophilia. 2005 Sep;11(5):481-91. PMID: 16128892. 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. |
| OMIM | RCV000010981 | SCV000031208 | pathogenic | Hereditary factor VIII deficiency disease | 1992-04-01 | no assertion criteria provided | literature only |