Submissions for variant NM_000132.4(F8):c.2149C>T (p.Arg717Trp)

gnomAD frequency: 0.00002  dbSNP: rs137852435

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002281701	SCV000883823	pathogenic	not provided	2023-04-17	criteria provided, single submitter	clinical testing	The F8 c.2149C>T; p.Arg717Trp variant (rs137852435), also known as Arg698Trp for legacy nomenclature, is reported in several patients diagnosed with mild hemophilia A (Diamond 1992, Gebhart 2018, Rudzki 1996, see Factor VIII variant database and references therein). This variant is reported in ClinVar (Variation ID: 10245) and is found in the general population with a low overall allele frequency of 0.001% (2/176848 alleles, including 1 hemizygote) in the Genome Aggregation Database. The arginine at codon 717 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.916). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII variant database: http://www.factorviii-db.org/advance_search_results.php 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. 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. PMID: 29388750. Rudzki Z et al. Mutations in a subgroup of patients with mild haemophilia A and a familial discrepancy between the one-stage and two-stage factor VIII:C methods. Br J Haematol. 1996; 94(2):400-6. PMID: 8759905.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851937	SCV000899321	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851590	SCV000899322	likely pathogenic	Abnormality of coagulation	2019-02-01	criteria provided, single submitter	research
Mendelics	RCV002247321	SCV002519673	pathogenic	Thrombophilia, X-linked, due to factor 8 defect	2022-05-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000010958	SCV002556585	likely pathogenic	Hereditary factor VIII deficiency disease	2019-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV002281701	SCV002571536	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R698W); This variant is associated with the following publications: (PMID: 19473423, 8759905, 29388750, 23812942, 10404764, 15810915, 29296726, 31064749, 1301932, 18691168)
Fulgent Genetics, Fulgent Genetics	RCV002490350	SCV002801784	pathogenic	Hereditary factor VIII deficiency disease; Thrombophilia, X-linked, due to factor 8 defect	2022-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000010958	SCV004223406	pathogenic	Hereditary factor VIII deficiency disease	2023-11-07	criteria provided, single submitter	clinical testing	Variant summary: F8 c.2149C>T (p.Arg717Trp) 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 1.7e-05 in 181533 control chromosomes (gnomAD). c.2149C>T (also known as Arg698Trp) has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (examples: Gilmore_2010, Downes_2019). These data indicate that the variant is very likely to be associated with disease. In addition, other missense variants at the same codon, R717L and R717Q, has been classified as pathogenic in ClinVar, indicating the arginine residue is critical for F8 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 20148980, 31064749). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000010958	SCV004809806	uncertain significance	Hereditary factor VIII deficiency disease	2024-04-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002281701	SCV005074488	likely pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	F8: PM1, PM2, PM5, PS4:Moderate
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000010958	SCV005398821	pathogenic	Hereditary factor VIII deficiency disease	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is associated with haemophilia A (MIM#306700), whereas gain of function due to copy number variations is associated with thrombophilia 13, X-linked, due to factor VIII defect (MIM#301071) (PMIDs: 23403259, 33275657). (I) 0108 - This gene is associated with both recessive and dominant disease. X-linked recessive inheritance is associated with haemophilia A (MIM#306700), whereas thrombophilia 13, X-linked, due to factor VIII defect (MIM#301071) has been reported with X-linked dominant inheritance (OMIM, PMID: 33275657). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygotes, 0 homozygotes, 2 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (4 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated plastocyanin-like 4 and F5/8 type A 2 domains (UniProt). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative changes, p.(Arg717Gln) and p.(Arg717Leu) have been reported as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar). They have also been reported in multiple affected individuals (EAHAD F8 database). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar). It has also been reported in many individuals with mild haemophilia A (EAHAD F8 database, PMID: 18691168). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000010958	SCV000031185	pathogenic	Hereditary factor VIII deficiency disease	1992-01-01	no assertion criteria provided	literature only