ClinVar Miner

Submissions for variant NM_000132.4(F8):c.2150G>A (p.Arg717Gln)

gnomAD frequency: 0.00005  dbSNP: rs942909873
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV003656150 SCV001157362 pathogenic not provided 2023-08-25 criteria provided, single submitter clinical testing The F8 c.2150G>A; p.Arg717Gln variant (rs942909873), also known as Arg698Gln, has been reported in multiple individuals with mild hemophilia A (see link to F8 database and references therein, David 2006). It is observed in the general population at a low overall frequency of 0.0017% (3/181547 alleles, 1 hemizygote) in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at residue 717 is highly conserved, and other missense variants at this position (p.Arg717Trp, p.Arg717Leu, and p.Arg717Pro) have also been reported in individuals with hemophilia A (see link to F8 database and references therein, Markoff 2009). Based on the available information, the p.Arg717Gln variant is considered pathogenic. REFERENCES Factor VIII variant 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 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; 15(4):932-41. PMID: 19473423
Mendelics RCV002249609 SCV002519671 pathogenic Thrombophilia, X-linked, due to factor 8 defect 2022-05-04 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV001000480 SCV002761868 likely pathogenic Hereditary factor VIII deficiency disease 2022-02-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002479189 SCV002781842 pathogenic Hereditary factor VIII deficiency disease; Thrombophilia, X-linked, due to factor 8 defect 2022-05-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001000480 SCV003934292 pathogenic Hereditary factor VIII deficiency disease 2023-05-04 criteria provided, single submitter clinical testing Variant summary: F8 c.2150G>A (p.Arg717Gln) results in a conservative amino acid change in the encoded protein sequence. Four 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 181547 control chromosomes (gnomAD). c.2150G>A has been reported in the literature in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A) (examples: Oldenburg_2001, David_2006, Markoff_2009, Eckhardt_2013, Provaznikova_2015). 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. In addition, other missense variants at the same codon, R717L and R717W, 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: 16769589, 23926300, 25824987, 19473423, 11179760, 25955082). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

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