ClinVar Miner

Submissions for variant NM_000132.4(F8):c.5096A>T (p.Tyr1699Phe)

gnomAD frequency: 0.00001  dbSNP: rs28935203
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV002508187 SCV000603515 pathogenic not provided 2023-10-25 criteria provided, single submitter clinical testing The F8 c.5096A>T; p.Tyr1699Phe variant (rs28935203), also known as Tyr1680Phe, is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (see link to FVIII database and references therein). This variant is reported in ClinVar (Variation ID: 10115), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. tyrosine at codon 1699 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.779). Based on available information, the p.Tyr1699Phe variant is considered to be pathogenic. References: Link to variant in FVIII variant database: http://www.factorviii-db.org/
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000010828 SCV001477509 pathogenic Hereditary factor VIII deficiency disease 2020-12-31 criteria provided, single submitter clinical testing
GeneDx RCV002508187 SCV002817842 pathogenic not provided 2022-06-28 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Pezeshkpoor et al., 2019; van den Biggelaar et al., 2011); Also known as (p.Y1680F); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19473423, 24108539, 10368977, 1554716, 1898735, 21940821, 11857744, 8547094, 17958741, 30997536, 27378673, 33552050, 32791533, 32232366, 24452774, 21909383, 2105906, 18691168, 19302446, 33314404, 27629384, 32299908, 1908096)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000010828 SCV004241319 pathogenic Hereditary factor VIII deficiency disease 2023-12-19 criteria provided, single submitter clinical testing Variant summary: F8 c.5096A>T (p.Tyr1699Phe) results in a 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 5.5e-06 in 180470 control chromosomes. c.5096A>T has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 23926300). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV004975259 SCV005584257 pathogenic Inborn genetic diseases 2024-08-14 criteria provided, single submitter clinical testing The c.5096A>T (p.Y1699F) alteration is located in exon 14 (coding exon 14) of the F8 gene. This alteration results from a A to T substitution at nucleotide position 5096, causing the tyrosine (Y) at amino acid position 1699 to be replaced by a phenylalanine (F). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/180470) total alleles studied, with 0 hemizygotes. The highest observed frequency was 0.001% (1/80944) of European (non-Finnish) alleles. This variant has been reported in multiple individuals with hemophilia A (Higuchi, 1990; Nance, 2013; Eckhardt, 2013; Pavlova, 2014; Nance, 2016). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing F8 function, this variant showed functionally abnormal results (van den Biggelaar, 2011; Pahl, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM RCV000010828 SCV000031055 pathogenic Hereditary factor VIII deficiency disease 1990-01-01 no assertion criteria provided literature only

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