Submissions for variant NM_000132.4(F8):c.6104T>C (p.Val2035Ala)

dbSNP: rs1603432906

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852173	SCV000899829	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001803976	SCV002047722	pathogenic	Hereditary factor VIII deficiency disease	2020-11-02	criteria provided, single submitter	clinical testing	The F8 c.6104T>C; p.Val2035Ala variant (rs1603432906), also known as Val2016Ala in traditional nomenclature, is reported in the literature in several individuals and families with mild to moderate hemophilia A (Green 2008, Repesse 2007, Rydz 2013, Waseem 1999). Additionally, other variants at this codon (p.Val2035Glu, p.Val2035Gly, p.Val2035Met) have been reported in individuals with hemophilia A (see link to F8 database and references therein, Rydz 2013).The c.6104T>C; p.Val2035Ala variant is listed in the ClinVar database (Variation ID: 627347) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 2035 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.950). Based on available information, this variant is considered to be pathogenic. References: Link to F8 database: https://f8-db.eahad.org/index.php Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. Repesse Y et al. Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development. J Thromb Haemost. 2007 Jul;5(7):1469-76. Rydz N et al. The Canadian "National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013 Dec;88(12):1030-4. doi: 10.1002/ajh.23557. Waseem NH et al. Start of UK confidential haemophilia A database: analysis of 142 patients by solid phase fluorescent chemical cleavage of mismatch. Haemophilia Centres. Thromb Haemost. 1999 Jun;81(6):900-5.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001803976	SCV002515603	pathogenic	Hereditary factor VIII deficiency disease		no assertion criteria provided	clinical testing