ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.2149C>T (p.Arg717Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(6); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000132.4(F8):c.2149C>T (p.Arg717Trp)
Variation ID: 10245 Accession: VCV000010245.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154931641 (GRCh38) [ NCBI UCSC ] X: 154159916 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000132.4:c.2149C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Arg717Trp missense NC_000023.11:g.154931641G>A NC_000023.10:g.154159916G>A NG_011403.2:g.96083C>T LRG_555:g.96083C>T LRG_555t1:c.2149C>T LRG_555p1:p.Arg717Trp P00451:p.Arg717Trp - Protein change
- R717W
- Other names
- F8, ARG698TRP
- R698W
- Canonical SPDI
- NC_000023.11:154931640:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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F8 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
902 | 1171 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Apr 4, 2024 | RCV000010958.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851590.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851937.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002247321.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 17, 2023 | RCV002281701.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2022 | RCV002490350.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Abnormality of coagulation
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899322.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1:
Sex: male
Ethnicity/Population group: European
Observation 2:
Sex: male
Ethnicity/Population group: European
Observation 3:
Sex: male
Ethnicity/Population group: European
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Hereditary factor IX deficiency disease
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899321.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1: Observation 2:
Sex: male
Ethnicity/Population group: Other
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia, X-linked, due to factor 8 defect
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002519673.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(Dec 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor VIII deficiency disease
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556585.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Mar 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia, X-linked, due to factor 8 defect
Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002801784.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883823.4
First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024 |
Comment:
The F8 c.2149C>T; p.Arg717Trp variant (rs137852435), also known as Arg698Trp for legacy nomenclature, is reported in several patients diagnosed with mild hemophilia A (Diamond 1992, … (more)
The F8 c.2149C>T; p.Arg717Trp variant (rs137852435), also known as Arg698Trp for legacy nomenclature, is reported in several patients diagnosed with mild hemophilia A (Diamond 1992, Gebhart 2018, Rudzki 1996, see Factor VIII variant database and references therein). This variant is reported in ClinVar (Variation ID: 10245) and is found in the general population with a low overall allele frequency of 0.001% (2/176848 alleles, including 1 hemizygote) in the Genome Aggregation Database. The arginine at codon 717 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.916). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII variant database: http://www.factorviii-db.org/advance_search_results.php Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992; 1(3):248-57. PMID: 1301932. Gebhart J et al. High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB). Haemophilia. 2018 May;24(3):405-413. PMID: 29388750. Rudzki Z et al. Mutations in a subgroup of patients with mild haemophilia A and a familial discrepancy between the one-stage and two-stage factor VIII:C methods. Br J Haematol. 1996; 94(2):400-6. PMID: 8759905. (less)
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Uncertain significance
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809806.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Sep 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002571536.2
First in ClinVar: Sep 17, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R698W); This variant is associated with the … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R698W); This variant is associated with the following publications: (PMID: 19473423, 8759905, 29388750, 23812942, 10404764, 15810915, 29296726, 31064749, 1301932, 18691168) (less)
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Pathogenic
(Nov 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223406.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: F8 c.2149C>T (p.Arg717Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: F8 c.2149C>T (p.Arg717Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 181533 control chromosomes (gnomAD). c.2149C>T (also known as Arg698Trp) has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (examples: Gilmore_2010, Downes_2019). These data indicate that the variant is very likely to be associated with disease. In addition, other missense variants at the same codon, R717L and R717Q, has been classified as pathogenic in ClinVar, indicating the arginine residue is critical for F8 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 20148980, 31064749). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 01, 1992)
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no assertion criteria provided
Method: literature only
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HEMOPHILIA A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031185.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Diamond et al. (1992) found this mutation in a patient with mild hemophilia A (306700). The mutation is caused by a CGG-to-TGG transition at codon … (more)
Diamond et al. (1992) found this mutation in a patient with mild hemophilia A (306700). The mutation is caused by a CGG-to-TGG transition at codon 698 in exon 14 of the A2 domain, resulting in tryptophan for arginine-698. The C-to-T transition follows the rule of CG-to-TG mutations at CG dinucleotides. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Thrombin generation in haemophilia A patients with mutations causing factor VIII assay discrepancy. | Gilmore R | Haemophilia : the official journal of the World Federation of Hemophilia | 2010 | PMID: 20148980 |
Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. | Diamond C | Human mutation | 1992 | PMID: 1301932 |
Text-mined citations for rs137852435 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.