ClinVar Miner

Submissions for variant NM_000133.4(F9):c.344A>G (p.Tyr115Cys)

dbSNP: rs1603264727
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000172 SCV001156661 pathogenic not specified 2019-03-05 criteria provided, single submitter clinical testing The F9 c.344A>G; p.Tyr115Cys variant, also reported as Tyr69Cys, has been described in multiple individuals affected with severe hemophilia B (see link to F9 database and references therein, Hamasaki-Katagiri 2012). It is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 115 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered pathogenic. REFERENCES F9 database: http://www.factorix.org/ Hamasaki-Katagiri N et al. Analysis of F9 point mutations and their correlation to severity of haemophilia B disease. Haemophilia. 2012 Nov;18(6):933-40.
Labcorp Genetics (formerly Invitae), Labcorp RCV001858905 SCV002149064 pathogenic Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect 2023-05-01 criteria provided, single submitter clinical testing This variant is also known as p.Tyr69Cys. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects F9 function (PMID: 29993188). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt F9 protein function. ClinVar contains an entry for this variant (Variation ID: 810872). This missense change has been observed in individuals with hemophilia B (PMID: 7937052, 19699296, 22544209, 22639855, 23093250, 29993188). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 115 of the F9 protein (p.Tyr115Cys).

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