Submissions for variant NM_000132.4(F8):c.1094A>G (p.Tyr365Cys)

gnomAD frequency: 0.00007  dbSNP: rs375241473

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV001093532	SCV004363676	pathogenic	Hereditary factor VIII deficiency disease	2024-02-02	reviewed by expert panel	curation	The NM_000132.3(F8):c.1094A>G variant predicts a missense change, Tyr365Cys, in the a1 interdomain of FVIII protein, reported to impair activation and deactivation of the protein meeting PM1 criteria (PMID: 12139751). This variant does not meet the rarity population criteria. It is reported in multiple individuals (>32) in the literature (PMID: 29296726, PMID: 12139751, PMID: 21645180, PMID: 17445092, PMID: 21751985, PMID: 18691168, PMID: 18034822, PMID: 19456877, PMID: 15810915, PMID: 11857744). Of note, this variant is associated with discrepant factor VIII activity levels between the one-stage and two-stage, or chromogenic, assay, and individuals with factor VIII levels measured on a two-stage assay may be within the normal range (EAHAD/CDC Champs databases). Additionally, individuals with this variant may have a mild to no bleeding history. The variant has a REVEL score of 0.756 (threshold >0.6) meeting PP3 criteria. In summary, the variant meets criteria to be classified as pathogenic causing decreased factor VIII activity levels, but may have a lower penetrant bleeding phenotype. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Expert Panel for F8: PS4_Very Strong, PM1, PP4_Moderate, PP3.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003103835	SCV000883832	pathogenic	not provided	2023-04-24	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: http://f8-db.eahad.org/ 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 Laboratory Services, 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.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001093532	SCV002500865	pathogenic	Hereditary factor VIII deficiency disease		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003489854	SCV004241889	uncertain significance	not specified	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: F8 c.1094A>G (p.Tyr365Cys) results in a non-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 6.5e-05 in 183378 control chromosomes with a total of 6 hemizygotes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in F8 causing Factor VIII Deficiency (Hemophilia A) (6.5e-05 vs 0.0098), allowing no conclusion about variant significance. c.1094A>G has been reported in the literature in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A), individuals with prolonged PTT and reduced factor VIII activity but minimal or absent bleeding symptoms, individuals with unspecified conditions of coagulation (examples, Bowyer_2011, Cutler_2002, Downes_2019, Hill_2005, Kentsis_2009, SilvaPinto_2012). Most often, those individuals were reported to have reduced one-stage FVIII:C values but normal two-stage FVIII:C or FVIII:Ag values (Bowyer_2011, Hill_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Factor VIII Deficiency (Hemophilia A). Co-occurrences with other pathogenic variant(s) have been reported in an individual with severe Hemophilia A (F8 c.3870delA, p.Glu1292Argfs*16) and the carrier mom was unaffected, providing supporting evidence for a benign role (Kentsis_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21751985, 11857744, 31064749, 15810915, 19456877, 21645180, 37647632). ClinVar contains an entry for this variant (Variation ID: 618104). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003103835	SCV005325272	pathogenic	not provided	2024-03-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18034822, 36473488, 21645180, 12139751, 19456877, 23812942, 18691168, 17445092, 34355501, 31064749, 15810915, 21838755, 21175850, 21751985, 19473423, 11857744)
PreventionGenetics, part of Exact Sciences	RCV004745578	SCV005360148	pathogenic	F8-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The F8 c.1094A>G variant is predicted to result in the amino acid substitution p.Tyr365Cys. This variant, also known as Tyr346Cys for legacy nomenclature, has been reported to be causative for Factor VIII deficiency in multiple individuals (Cutler et al. 2002. PubMed ID: 11857744; Repessé et al. 2007. PubMed ID: 17445092; Green et al. 2008. PubMed ID: 18691168; Factor VIII database: https://www.factorviii-db.org/index.php). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.