Submissions for variant NM_000132.4(F8):c.5399G>A (p.Arg1800His)

dbSNP: rs137852442

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV000010987	SCV004363665	pathogenic	Hereditary factor VIII deficiency disease	2024-02-02	reviewed by expert panel	curation	The NM_000132.4(F8):c.5399G>A (p.Arg1800His) variant is completely absent from gnomAD v2.1.1 and gnomAD v3.1.2, meeting the PM2_Supporting criteria. More than 17 individuals in the literature and 40 in the internal laboratory data are observed with hemophilia A ranging from mild to severe carrying the Arg1800His variant. More cases are available in the literature (EAHAD database reports 76 individuals); however, the threshold for PS4_VeryStrong (>8) and PP4_Moderate have been reached. This variant has been associated with discrepant factor VIII activity levels (PMID: 32232366). This variant has also been associated with inhibitor development to factor replacement therapy (CDC CHAMPS/EAHAD databases). The c.5399G>A (p.Arg1800His) missense variant has a REVEL score of 0.96 (>0.6), which meets the PP3 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_VeryStrong, PP4_Moderate, PP3, PM2_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000010987	SCV000603524	pathogenic	Hereditary factor VIII deficiency disease	2019-08-13	criteria provided, single submitter	clinical testing	The F8 c.5399G>A; p.Arg1800His variant (rs137852442), also known as p.Arg1781His using alternative nomenclature, has been reported in multiple patients with moderate to severe hemophilia A (Casana 2008, Higuchi 1991, Yada 2013, Factor VIII variant database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 1800 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. These predictions are consistent with activity measurements of patient samples with this variant, which exhibit 1-10% of normal clotting activity (Factor VIII variant database). Additionally, other amino acid substitutions at this codon (Cys, Gly, Leu, and Pro) have been reported in individuals with hemophilia A and are considered disease-causing (Factor VIII variant database). Based on available information, the p.Arg1800His variant is classified as pathogenic. References: Factor VIII variant database: http://www.factorviii-db.org/newstructure.php?aa_first=Arg&mut_id=1263&aa_last=His Casana P et al. Severe and moderate hemophilia A: identification of 38 new genetic alterations. Haematologica. 2008 Jul;93(7):1091-4. Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991; 88(16):7405-9. Yada K et al. The mild phenotype in severe hemophilia A with Arg1781His mutation is associated with enhanced binding affinity of factor VIII for factor X. Thromb Haemost. 2013; 109(6):1007-15.
GeneDx	RCV001552643	SCV001773367	pathogenic	not provided	2019-02-07	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies suggest a damaging effect; Presence of R1800H (reported as R1781H) resulted in a relative enhancement in association between FVIIIa and FX (Yada et al., 2013); This variant is associated with the following publications: (PMID: 33245802, 30507053, 23467620, 19817879, 27292088, 19473423, 1908096)
PreventionGenetics, part of Exact Sciences	RCV003430635	SCV004117894	pathogenic	F8-related disorder	2022-10-31	criteria provided, single submitter	clinical testing	The F8 c.5399G>A variant is predicted to result in the amino acid substitution p.Arg1800His. This variant, also described using legacy nomenclature as p.Arg1781His, has been reported in individuals with moderate to severe Hemophilia A (Higuchi et al. 1991. PubMed ID: 1908096; Casaña et al. 2008. PubMed ID: 18403393; Yada et al. 2013. PubMed ID: 23467620; Kars et al. 2021. PubMed ID: 34426522. Dataset S4; Factor VIII variant database: https://f8-db.eahad.org/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001552643	SCV005413472	likely pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	PP3, PP4, PP5, PM2_moderate, PS4_moderate
OMIM	RCV000010987	SCV000031214	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001552643	SCV001931040	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001552643	SCV001956746	pathogenic	not provided		no assertion criteria provided	clinical testing