ClinVar Genomic variation as it relates to human health

The F8 c.6967C>T; p.Arg2323Cys variant (rs137852473) is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (see link to FVIII database and references therein, Johnsen 2017, Lu 2018). This variant is reported in ClinVar (Variation ID: 10333), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2323 is highly conserved, and/ computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (Gly, His, Leu) have been reported in individuals with mild hemophilia and are considered pathogenic (FVIII database and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to FVIII database: http://www.factorviii-db.org 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. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298.

Variant summary: F8 c.6967C>T (p.Arg2323Cys) results in a non-conservative amino acid change located in the Coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 21864 control chromosomes. c.6967C>T has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (e.g. Baz_2021, Eckhardt_2013, Johnsen_2022, Miller_2012). These data indicate that the variant is very likely to be associated with disease. Additionally, other missense variants in the same residue have been associated with Haemophilia A in HGMD and Clinvar (R2323G, R2323H, R2323L and R2323P). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34272389, 23926300, 29381227, 22103590). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The F8 c.6967C>T missense variant has been classified as Likely Pathogenic (PM2_supporting, PS4_moderate, PM5, PP4). The c.6967C>T variant is in gnomAD at very low frequency (PM2_supporting) however, the variant is prevalent in affected individuals (PS4_moderate). This variant has been reported in PMID: 32897612 and 35014236 in a patient with severe and moderate haemophilia A, respectively. This variant is a missense change at an amino acid residue where a different missense change has been seen before; R2323G, R2323H, R2323P and R2323L as reported in ClinVar and/or HGMD (PM5). This variant is located in the functional C2 domain which is largely responsible for vWF and platelet membrane surface binding, and has also been shown to participate in binding to factor Xa and thrombin (PMID 15471879). The patient's phenotype and FVIII bioassay levels are consistent with the specific genetic aetiology (PP4). This variant has been reported in dbSNP (rs137852473), HMGD as disease causing (CM910153) and in ClinVar as pathogenic (ClinVar variant ID:10333).