ClinVar Genomic variation as it relates to human health

PP3, PM2, PS4_moderate, PP1_strong

The F8 6371A>G; p.Tyr2124Cys variant (rs137852459), also known as Tyr2105Cys, has been described in the literature in numerous individuals with mild/moderate hemophilia A (Naylor 1993, Margaglione 2008, Johnsen 2017, Williams 2015, F8 database), and it is also reported in ClinVar (Variation ID: 10310). This variant is only observed on one allele (one hemizygote) in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 2124 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.97). Taken together, this variant is considered pathogenic. References: Naylor JA et al. Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients. Hum Mol Genet. 1993 Jan;2(1):11-7. PMID: 8490618 Margaglione M et al. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008 May;93(5):722-8. PMID: 18387975 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 Williams VK et al. Extensive bleeding due to an inhibitor in a haemophilia A patient with a Tyr2105Cys mutation: elimination of the inhibitor with rituximab. Pathology. 2015 Oct;47(6):586-8. PMID: 26308136 Link to F8 database: https://f8-db.eahad.org/VariantPage.php?ID=1594&hash=2a3f84a96bdd139de9f11adfe4865fbc

The F8 c.6371A>G variant is classified as Likely Pathogenic (PS4_Moderate, PM1, PM2, PP3) The F8 c.6371A>G variant is a single nucleotide change in exon 22/26 of the F8 gene, which is predicted to change the amino acid tyrosine at position 2124 in the protein to cysteine. The variant has been reported in numerous individuals with a clinical presentation of mild to severe haemophilia as reported in the EAHAD F8 Variant database (PS4_Mod). Note that this variant is also reported in the literature as Tyr2105Cys.This variant is absent from population databases (PM2). This variant is located in the Factor VIII C domain which contains key binding sites for von Willebrand factor (vWF) and phospholipid membranes (PMID: 10910913) (PM1). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs137852459) and in the HGMD database: CM930235. It has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 10310).

Variant summary: F8 c.6371A>G (p.Tyr2124Cys) results in a non-conservative amino acid change located in the Coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183296 control chromosomes. c.6371A>G has been reported in the literature in multiple individuals affected with milder/non-severe Factor VIII Deficiency (Hemophilia A). 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: 23926300, 22103590). ClinVar contains an entry for this variant (Variation ID: 10310). Based on the evidence outlined above, the variant was classified as pathogenic.