ClinVar Miner

Submissions for variant NM_000132.3(F8):c.6346T>C (p.Tyr2116His) (rs781870586)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000907 SCV001157991 uncertain significance Hereditary factor VIII deficiency disease 2018-11-08 criteria provided, single submitter clinical testing The F8 c.6346T>C; p.Tyr2116His variant (rs781870586), to our knowledge, is not described in the medical literature or in gene-specific databases. It is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 2116 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. This variant is located in the C1 domain, and functional analyses of variants in this region have demonstrated reduced binding to von Willebrand factor (Jacquemin 2000), demonstrating the importance of this region in normal protein function. Additionally, several surrounding variants (p.Arg2109Cys, p.Leu2115Pro, p.Ile2117Phe, p.Ile2117Ser, p.Ser2118Pro, p.Gln2119Arg, p.Phe2120Cys, p.Phe2120Leu) have been described in individuals with mild to moderate hemophilia A and are considered pathogenic (see link to F8 database and references therein). However, due to the lack of clinical and functional data regarding the p.Tyr2116His variant, its clinical significance cannot be determined with certainty. REFERENCES Link to F8 database: Jacquemin M et al. A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Blood. 2000 Aug 1;96(3):958-65.

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