Submissions for variant NM_000132.4(F8):c.5954G>A (p.Arg1985Gln)

gnomAD frequency: 0.00001  dbSNP: rs1490417405

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001700302	SCV000883825	pathogenic	not provided	2022-10-18	criteria provided, single submitter	clinical testing	The F8 c.5954G>A; p.Arg1985Gln variant, also known as Arg1966Gln for legacy nomenclature, is reported in the literature in multiple individuals affected with mild hemophilia A (David 2006, Fernandez-Lopez 2005, Green 2008, Jayandharan 2005, Liu 1998, Liu 2002, Theophilus 2001). This variant is reported in ClinVar (Variation ID: 618098), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1985 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.687). Based on available information, this variant is considered to be pathogenic for mild hemophilia A. References: Factor VIII database: http://www.factorviii-db.org David D et al. The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients. Haematologica. 2006; 91(6):840-3. PMID: 16769589. Fernandez-Lopez O et al. The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations. Haematologica. 2005; 90(5):707-10. PMID: 15921397. Green P et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008; 143(1):115-28. PMID: 18691168. Jayandharan G et al. Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions. Haemophilia. 2005; 11(5):481-91. PMID: 16128892. Liu M et al. A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins. Br J Haematol. 1998; 103(4):1051-60. PMID: 9886318. Liu M et al. Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses. Thromb Haemost. 2002; 87(2):273-6. PMID: 11858487. Theophilus B et al. Site and type of mutations in the factor VIII gene in patients and carriers of haemophilia A. Haemophilia. 2001; 7(4):381-91. PMID: 11442643.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852168	SCV000899824	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
Genetics and Molecular Pathology, SA Pathology	RCV000756107	SCV002761634	likely pathogenic	Hereditary factor VIII deficiency disease	2020-06-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001700302	SCV004225716	uncertain significance	not provided	2022-07-12	criteria provided, single submitter	clinical testing	PP5, PM2, PS4_moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000756107	SCV005422803	pathogenic	Hereditary factor VIII deficiency disease	2024-10-30	criteria provided, single submitter	clinical testing	Variant summary: F8 c.5954G>A (p.Arg1985Gln) results in a conservative amino acid change located in the Multicopper oxidase, C-terminal domain (IPR011706) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182940 control chromosomes. c.5954G>A has been reported in the literature in the presumed hemizygous state in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (example, Fernandez-Lopez_2005, Shinozawa_2021). 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: 15921397, 33254277). ClinVar contains an entry for this variant (Variation ID: 618098). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001700302	SCV001926842	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001700302	SCV001953827	pathogenic	not provided		no assertion criteria provided	clinical testing