Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001803658 | SCV002049506 | pathogenic | Hereditary factor VIII deficiency disease | 2021-04-06 | criteria provided, single submitter | clinical testing | The F8 c.6956dupC; p.Leu2320ValfsTer65 variant (rs1475873048), is reported in the literature in an individual affected with severe hemophilia A (see F8 database and references therein). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, another frameshift variant at this codon (c.6956_6957dupCACC, p.Leu2320ThrfsTer66) has been reported in individuals with severe hemophilia A and is considered pathogenic (Guo 2018). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII database: https://f8-db.eahad.org/index.php Guo Z et al. Spectrum of Molecular Defects in 216 Chinese Families With Hemophilia A: Identification of Noninversion Mutation Hot Spots and 42 Novel Mutations. Clin Appl Thromb Hemost. 2018 Jan;24(1):70-78. PMID: 28056528. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001803658 | SCV004803979 | likely pathogenic | Hereditary factor VIII deficiency disease | 2024-01-30 | criteria provided, single submitter | clinical testing | Variant summary: F8 c.6956dupC (p.Leu2320ValfsX65) causes a frameshift which results in an extension of the protein. The variant was absent in 182967 control chromosomes (gnomAD). c.6956dupC has been reported in the literature in at least one individual affected with Factor VIII Deficiency (Hemophilia A) (e.g., Johnsen_2017, F8 database (https://dbs.eahad.org/)). FVIII:C activity in this individual was also reported to be <1%. The following publication have been ascertained in the context of this evaluation (PMID: 29296726). ClinVar contains an entry for this variant (Variation ID: 1330566). Additionally, several upstream and downstream variants resulting in the same protein extension (e.g., c.6988dupC/p.Gln2330Profs*55, c.6994dupT/p.Trp2332Leufs*53, c.7006dupA/p.Ile2336Asnfs*49) have been reported in the patients with Hemophilia A (HGMD). Based on the evidence outlined above, the variant was classified as likely pathogenic. |