Submissions for variant NM_000132.4(F8):c.5123G>A (p.Arg1708His)

gnomAD frequency: 0.00002  dbSNP: rs111033614

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851813	SCV000899781	pathogenic	Abnormality of coagulation	2019-02-01	criteria provided, single submitter	research
GeneDx	RCV001091839	SCV001804412	pathogenic	not provided	2024-05-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23711294, 23020595, 19719828, 11179760, 24452774, 26628308, 20331761, 1851341, 8485051, 27734074, 29388750, 1064749, 21707934, 31064749, 36007526, 19473423, 32166871)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000010979	SCV002050209	pathogenic	Hereditary factor VIII deficiency disease	2021-03-17	criteria provided, single submitter	clinical testing	The F8 c.5123G>A; p.Arg1708His variant (rs111033614), also known as p.Arg1689His, is reported in the literature in multiple individuals affected with mild hemophilia A (Gebhart 2018, Schwaab 1995, Factor VIII variant database and references therein), including at least one individual in which it arose de novo (Williams 2012). F8 activity in hemizygous individuals with this variant have been measured between 7%-43% of normal (Factor VIII variant database and references therein). This variant is found on only two chromosomes in the Genome Aggregation Database (2/180265 alleles), indicating it is not a common polymorphism. The arginine at codon 1708 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.885). Additionally, other amino acid substitutions at this codon (p.Arg1708Ser, p.Arg1708Cys, p.Arg1708Leu) have been reported in individuals with hemophilia A and are considered pathogenic (Factor VIII variant database and references therein). Based on available information, the p.Arg1708His variant is considered to be pathogenic. References: Factor VIII variant database: https://f8-db.eahad.org/ 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. Schwaab R et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol. 1995 Oct;91(2):458-64. Williams VK et al. Investigation of inflicted injury in a young girl reveals mild haemophilia A and Turner's syndrome. Int J Lab Hematol. 2012 Feb;34(1):98-101.
Genetics and Molecular Pathology, SA Pathology	RCV000010979	SCV002556791	likely pathogenic	Hereditary factor VIII deficiency disease	2021-07-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001091839	SCV003831143	likely pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing
OMIM	RCV000010979	SCV000031206	pathogenic	Hereditary factor VIII deficiency disease	1993-03-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003914826	SCV004732490	pathogenic	F8-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The F8 c.5123G>A variant is predicted to result in the amino acid substitution p.Arg1708His. This variant (aka p.Arg1689His) has been reported in multiple individuals with mild hemophilia A or other bleeding disorders (Schwaab et al. 1991. PubMed ID: 1851341; Downes et al. 2019. PubMed ID: 31064749. Suppl3_SNV+INDEL; F8 database: https://www.factorviii-db.org/index.php). Different missense substitution at this same codon (p.Arg1708Cys; p.Arg1708Ser) have also been reported in patients with hemophilia A (Rydz et al. 2013. PubMed ID: 23913812; Lu et al. 2018. PubMed ID: 29381227) suggesting that amino acid residue p.Arg1708 is important for proper F8 protein function. This variant is reported in 0.0055% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.