ClinVar Miner

Submissions for variant NM_000132.3(F8):c.1094A>G (p.Tyr365Cys) (rs375241473)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001093532 SCV000883832 pathogenic Hereditary factor VIII deficiency disease 2020-08-12 criteria provided, single submitter clinical testing The F8 c.1094A>G; p.Tyr365Cys variant (rs375241473), also known as Tyr346Cys, is published in the medical literature and in gene-specific databases in several individuals with mild hemophilia (see link to FVIII database, Bowyer 2011, Cutler 2002, Hill 2005). This variant is found in the Genome Aggregation Database in the non-Finnish European populationwith an allele frequency of 0.015% (12/81864 alleles, including 6 hemizygotes). The tyrosine at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is considered pathogenic. References: Link to F8 database: Bowyer AE et al. p.Tyr365Cys change in factor VIII: haemophilia A, but not as we know it. Br J Haematol. 2011 Sep;154(5):618-25. Cutler JA et al. The identification and classification of 41 novel mutations in the factor VIII gene (F8C). Hum Mutat. 2002 Mar;19(3):274-8. Hill M et al. Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype. Haemophilia. 2005 Mar;11(2):133-41.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851582 SCV000899296 pathogenic Hereditary factor IX deficiency disease 2019-02-01 criteria provided, single submitter research
Versiti Diagnostic Laboratories,Versiti, Inc RCV001093532 SCV001250580 likely benign Hereditary factor VIII deficiency disease 2020-01-28 criteria provided, single submitter clinical testing The missense variant F8 c.1094A>G, p.Tyr365Cys (p.Y365C; legacy p.Y346C) in exon 8 changes amino acid tyrosine at codon 365 to cysteine (also described as Y346C). The tyrosine at this residue is not well conserved among species. This amino acid change occurs in the a1 interdomain region which plays an important role in activation and degradation of FVIII (Mumford, 2002). Pathogenic variants in F8 are associated with X-linked hemophilia A characterized by mild to severe bleeding due to a quantitative or qualitative deficiency in factor VIII. This variant has been previously described in individuals reported to have hemophilia A, most often mild (Cutler, 2002; Green, 2008; Repesse, 2007); however, it has also been reported in individuals that presented with prolonged APTT without a clinically significant bleeding disorder or with bleeding diathesis that was less severe than expected in individuals or carriers of mild hemophilia A (Mumford, 2002; Lyall, 2008; Kentsis, 2009; Bowyer 2011) and/or individuals who were found to have reduced one-stage FVIII:C values but normal two-stage FVIII:C or FVIII:Ag values (Mumford, 2002; Lyall, 2008; Hill, 2005; Bowyer 2011). The minor allele frequency in the general population is 0.00006645 with an elevated allele frequency of 0.0001388 in the European population and 1 observation in a hemizygous state (gnomAD), which is more frequent than expected for hemophilia A. No functional data is available for this variant. Studies of FVIII protein purified from patient plasma showed decreased activation to FVIIIa at low thrombin concentrations (<1nmol/l) and increased decay of FVIIIa in a molar excess of thrombin (25nmol/l) (Mumford, 2002); the one-stage assay would be most sensitive to this due to the minimal time allowed between thrombin activation and clotting . Multiple lines of in silico computational evidence (Condel, Polyphen2, Mutation Taster, SIFT) predict the variant to be damaging; however, the accuracy of these tools is unknown. In summary, although individuals who are heterozygous or hemizygous for this variant may exhibit reduced FVIII activity levels by one-stage assays, this variant does not appear to result in increased risk for bleeding; therefore, the collective evidence supports F8 c.1094A>G, p.Tyr365Cys as a likely benign variant with respect to hemophilia A.
Illumina Clinical Services Laboratory,Illumina RCV001093532 SCV001331109 uncertain significance Hereditary factor VIII deficiency disease 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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