Submissions for variant NM_000132.4(F8):c.6932C>A (p.Pro2311His)

gnomAD frequency: 0.00001  dbSNP: rs1047644991

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851860	SCV000899877	likely pathogenic	Abnormality of coagulation	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001803975	SCV002048988	likely pathogenic	Hereditary factor VIII deficiency disease	2020-12-11	criteria provided, single submitter	clinical testing	The F8 c.6932C>A; p.Pro2311His variant (rs1047644991) is reported in the literature in multiple individuals affected with mild hemophilia A (see link to F8 database and references therein, Downes 2019, Gebhart 2018). In vitro functional analyses demonstrate that individuals with this variant have factor VIII activity between 7-37% (F8 database, Gebhart 2018). This variant is reported in ClinVar (Variation ID: 627123). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 2311 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.639). Additionally, another variants at this codon (c.6931C>T; p.Pro2311Ser) has been reported in individuals with mild hemophilia A (F8 database). Based on available information, the p.Pro2311His variant is considered to be likely pathogenic. References: F8 Variant Database: https://f8-db.eahad.org Downes K et al. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood. 2019 Dec 5;134(23):2082-2091 Gebhart J et al. High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB). Haemophilia. 2018 May;24(3):405-413.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001803975	SCV005394767	pathogenic	Hereditary factor VIII deficiency disease	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: F8 c.6932C>A (p.Pro2311His) 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 was absent in 183208 control chromosomes (gnomAD). c.6932C>A has been reported in the literature in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A), i.e. with a factor VIII residual activity between 20 and 30% (e.g. Rosset_2013, Lannoy_2015, Gebhart_2018). These data indicate that the variant is very likely to be associated with disease. 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: 25824987, 23711237, 29388750). ClinVar contains an entry for this variant (Variation ID: 627123). Based on the evidence outlined above, the variant was classified as pathogenic.