Submissions for variant NM_000132.4(F8):c.1834C>T (p.Arg612Cys)

gnomAD frequency: 0.00001  dbSNP: rs137852428

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV000010949	SCV004363667	pathogenic	Hereditary factor VIII deficiency disease	2024-02-09	reviewed by expert panel	curation	The c.1834C>T (p.Arg612Cys) variant is present in 3 hemizygotes in gnomAD v2.1.1, so PM2_Supporting in not met. The REVEL score of 0.88 which meets PP3 criteria (threshold >0.6). Thirty-two patients were reported with mild-moderate hemophilia A in a single publication and over 100 individuals were identified in the My Life Our Future Cohort, meeting F8 phenotype criteria for PP4_Moderate and PS4_Very strong (PMID: 18691168, 29296726). This variant has been associated with mostly mild, but also moderate and severe, hemophilia A with and without inhibitors to factor replacement therapies. This may be in part because the variant has also been associated with discrepant factor VIII activity levels, with chromogenic assays (two-stage) being 2-fold lower than one stage assays (EAHAD database; PMID: 32232366). The variant has been reported to segregate with hemophilia A in greater than 6 meioses across two families (PP1_Strong; PMID: 9292523). This variant has also been found to have at least one de novo occurrence in the mother of a proband, where the proband was found to have the unaffected maternal grandfather's allele via haplotype analysis (PS2; PMID: 9292523). Additionally, this variant has been reported in patients with and without a history of inhibitors to factor replacement products (EAHAD database). 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: PS2, PS4_Very strong, PP1_Strong, PP3 and PP4_Moderate.
GeneDx	RCV000413577	SCV000491183	pathogenic	not provided	2024-03-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R612C reduces factor VIII activity, and leads to intracellular accumulation and subsequent degradation of the F8 protein (PMID: 10691849); This variant is associated with the following publications: (PMID: 12195713, 11858487, 7794769, 8281136, 35014236, 31064749, 1908096, 7728145, 15682412, 1301932, 9569189, 21251204, 19473423, 11554935, 26057490, 11341489, 10404764, 29296726, 33245802, 32897612, 35047849, 10691849)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000413577	SCV000603514	pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing	The F8 c.1834C>T; p.Arg612Cys variant (rs137852428), also known as Arg593Cys, is reported in multiple patients associated with mild or moderate hemophilia (See Factor VIII database and references therein, Antonarakis 1995, Diamond 1992, Higuchi 1991, Markoff 2009, Trampus Bajika 2015). This variant is reported in ClinVar (Variation ID: 10236), and found in the general Latino/Admixed American population with an allele frequency of 0.01% (4/27431 alleles, including 3 hemizygotes) in the Genome Aggregation Database. The arginine at codon 612 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.808). Based on available information, this variant is considered to be pathogenic. References: Factor VIII variant database: https://f8-db.eahad.org/index.php Antonarakis SE et al. Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat. 1995;5(1):1-22. PMID: 7728145. Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992;1(3):248-57. PMID: 1301932. 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 Aug 15;88(16):7405-9. PMID: 1908096. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. PubMed: 19473423. Trampus Bakija A et al. Specific and global coagulation tests in patients with mild haemophilia A with a double mutation (Glu113Asp, Arg593Cys). Blood Transfus. 2015 Oct;13(4):622-30. PubMed: 26057490.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851933	SCV000899317	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000413577	SCV001713980	pathogenic	not provided	2022-04-06	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PP5, PM3_supporting, PS3, PS4_moderate
Mendelics	RCV002247320	SCV002519675	pathogenic	Thrombophilia, X-linked, due to factor 8 defect	2022-05-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000010949	SCV002556860	pathogenic	Hereditary factor VIII deficiency disease	2022-06-15	criteria provided, single submitter	clinical testing	PS3, PS4, PP3, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000010949	SCV005040006	pathogenic	Hereditary factor VIII deficiency disease	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: F8 c.1834C>T (p.Arg612Cys) results in a non-conservative amino acid change in 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 2.2e-05 in 183438 control chromosomes (gnomAD). c.1834C>T (also known as Arg593Cys) has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (examples: Eckhardt_2009, and Rosset_2013). 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: 23711237, 19548904). ClinVar contains an entry for this variant (Variation ID: 10236). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004540992	SCV005040802	pathogenic	Familial aortopathy	2024-03-08	criteria provided, single submitter	clinical testing
OMIM	RCV000010949	SCV000031176	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000010949	SCV002515615	pathogenic	Hereditary factor VIII deficiency disease		no assertion criteria provided	research