Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001802297 | SCV002050143 | pathogenic | Hereditary factor VIII deficiency disease | 2020-11-30 | criteria provided, single submitter | clinical testing | The F8 c.2048A>G; p.Tyr683Cys variant, also known as Tyr664Cys, is reported in the literature in at least 22 individuals affected with severe hemophilia A (See link to F8 database and references therein, Villarreal-Martinez 2020). In vitro functional analyses demonstrate that almost all individuals with this variant had <1% factor VIII activity (see link to F8 database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 683 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.696). Based on available information, this variant is considered to be pathogenic. REFERENCES Link to F8 database: https://f8-db.eahad.org/index.php Villarreal-Martinez L et al. Molecular genetic diagnosis by next-generation sequencing in a cohort of Mexican patients with haemophilia and report of novel variants. Blood Cells Mol Dis. 2020 Jul;83:102423. |
| 3billion, |
RCV001802297 | SCV003841566 | pathogenic | Hereditary factor VIII deficiency disease | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.83). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with F8-related disorder (ClinVar ID: VCV001330638 / PMID: 11554935). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11554935, 12325022, 12871415, 18403393, 19719548, 21070499, 29296726). Different missense changes at the same codon (p.Tyr683Asn, p.Tyr683His, p.Tyr683Ser) have been reported to be associated with F8-related disorder (PMID: 22958177, 23926300, 9886318). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001802297 | SCV005185312 | pathogenic | Hereditary factor VIII deficiency disease | 2024-05-08 | criteria provided, single submitter | clinical testing | Variant summary: F8 c.2048A>G (p.Tyr683Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183248 control chromosomes. c.2048A>G has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (example: Timur_2001, Casana_2008, Villarreal-Martnez_2020, Xue_2020, Borras_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32224444, 20528906, 34708896, 11554935, 18403393). ClinVar contains an entry for this variant (Variation ID: 1330638). Based on the evidence outlined above, the variant was classified as pathogenic. |