Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001002198 | SCV005431481 | uncertain significance | Hereditary factor VIII deficiency disease | 2024-10-11 | reviewed by expert panel | curation | The c.5815G>C variant in F8 is a missense variant predicted to cause substitution of Alanine by Proline at amino acid 1939 in the last codon in exon 17, affecting the A3 domain of Factor VIII. It is reported affecting one individual in EAHAD with FVIII:C 1-stage =<1% with full gene sequencing and deletion/duplication analysis done, therefore it meets the phenotypic criteria for PP4_Moderate to be applied (PMID: 29296726). This variant has been reported in 1 proband with severe hemophilia A. However, PS4_Supporting cannot be applied because the individual also has a c.5493C>G i.e., p.(Thr1831Thr) variant (PMID: 30793713). The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.6, and Splice AI gives a score of 0.94 for donor loss, which is above the threshold of 0.5 set by the CFD VCEP and is evidence that correlates with impact to F8 function (PP3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP for F8 (version 1.0.0, released 10/5/2023): PP4_Moderate, PP3_Supporting, PM2_Supporting. |
| ARUP Laboratories, |
RCV001002198 | SCV001160071 | likely pathogenic | Hereditary factor VIII deficiency disease | 2018-11-09 | criteria provided, single submitter | clinical testing | The F8 c.5815G>C; p.Ala1939Pro variant, to our knowledge, is not described in the medical literature or in gene-specific databases. It is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 1939 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. This variant also occurs at the last nucleotide in the exon and is predicted to weaken the nearby canonical donor splice site (Alamut v.2.11). Additional variants at this position (p.Ala1939Glu, p.Ala1939Ser, and p.Ala1939Thr) have been described in individuals affected with severe hemophilia A and are considered pathogenic (see link to F8 database and references therein). Based on available information, the p.Ala1939Pro variant is considered likely pathogenic. REFERENCES Link to F8 database: http://www.factorviii-db.org/ |
| Center for Genomic Medicine, |
RCV001002198 | SCV001622570 | uncertain significance | Hereditary factor VIII deficiency disease | 2021-04-28 | criteria provided, single submitter | research |