ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.5122C>T (p.Arg1708Cys)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000132.4(F8):c.5122C>T (p.Arg1708Cys)
Variation ID: 10114 Accession: VCV000010114.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154928668 (GRCh38) [ NCBI UCSC ] X: 154156943 (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 Mar 30, 2018 Oct 8, 2024 Nov 20, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000132.4:c.5122C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Arg1708Cys missense NC_000023.11:g.154928668G>A NC_000023.10:g.154156943G>A NG_011403.2:g.99056C>T LRG_555:g.99056C>T LRG_555t1:c.5122C>T LRG_555p1:p.Arg1708Cys P00451:p.Arg1708Cys - Protein change
- R1708C
- Other names
- F8, ARG1689CYS
- R1689C
- Canonical SPDI
- NC_000023.11:154928667: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) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
951 | 1225 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 20, 2020 | RCV000010826.15 | |
FACTOR VIII (EAST HARTFORD)
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Pathogenic (1) |
no assertion criteria provided
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May 1, 1992 | RCV000010827.4 |
Pathogenic (3) |
criteria provided, single submitter
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Apr 1, 2018 | RCV001092277.24 |
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
Help
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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Pathogenic
(Nov 20, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048842.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The F8 c.5122C>T; p.Arg1708Cys variant (rs111033613), also known as Arg1689Cys, is reported in the literature in multiple individuals affected with moderate hemophilia A (see link … (more)
The F8 c.5122C>T; p.Arg1708Cys variant (rs111033613), also known as Arg1689Cys, is reported in the literature in multiple individuals affected with moderate hemophilia A (see link to Factor VIII database and references therein). This variant is reported in ClinVar (Variation ID: 10114), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 1708 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.941). The arginine residue at this position is critical for the thrombin-mediated cleavage required to generate an activated F8 fragment (Pittman 1988), and p.Arg1708Cys variant prevents the processing of the F8 protein into the activated form (Arai 1990, Kamisue 1994). Additionally, other amino acid substitutions at this codon (p.Arg1708Ser, p.Arg1708His, p.Arg1708Leu) have been reported in individuals with hemophilia A and are considered pathogenic (Factor VIII database and references therein). Based on available information, this variant is considered to be pathogenic. References: Factor VIII variant database: http://f8-db.eahad.org/index.php Arai M et al. Characterization of a thrombin cleavage site mutation (Arg 1689 to Cys) in the factor VIII gene of two unrelated patients with cross-reacting material-positive hemophilia A. Blood. 1990 75(2):384-9. Kamisue S et al. Abnormal factor VIII Hiroshima: defect in crucial proteolytic cleavage by thrombin at Arg1689 detected by a novel ELISA. Br J Haematol. 1994 86(1):106-11. Pittman D et al. Proteolytic requirements for thrombin activation of anti-hemophilic factor (factor VIII). Proc Natl Acad Sci U S A. 1988 85(8):2429-33. (less)
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor VIII deficiency disease
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370095.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,PP5.
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Pathogenic
(Apr 01, 2018)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248698.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Jun 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Hereditary factor VIII deficiency disease
Affected status: yes
Allele origin:
germline
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Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Accession: SCV001424879.1
First in ClinVar: Nov 19, 2020 Last updated: Nov 19, 2020 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Causasians
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926361.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(May 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: SCV000031053.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 30, 2018 |
Comment on evidence:
In a patient with moderately severe hemophilia A (306700) of a CRM-positive type, Gitschier (1988) found a CGC-to-TGC change in codon 1708 in exon 14, … (more)
In a patient with moderately severe hemophilia A (306700) of a CRM-positive type, Gitschier (1988) found a CGC-to-TGC change in codon 1708 in exon 14, resulting in a change of arginine-1689 to cysteine. The mutation affects the thrombin cleavage site. The same mutation was subsequently found in additional patients (JH38, JH39) by Arai et al. (1990). Aly et al. (1992) found that cysteamine, which is known to modify mutant proteins with an arg-to-cys substitution, enhances the procoagulant activity of the mutant factor VIII, which they referred to as factor VIII-East Hartford. Aly and Hoyer (1992) demonstrated that the East Hartford mutant protein had procoagulant activity when separated from von Willebrand factor; this was taken to indicate that the dissociation of factor VIII from VWF is an essential effect of factor VIII light chain cleavage at arginine-1689. (less)
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Pathogenic
(May 01, 1992)
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no assertion criteria provided
Method: literature only
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FACTOR VIII (EAST HARTFORD)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031054.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 30, 2018 |
Comment on evidence:
In a patient with moderately severe hemophilia A (306700) of a CRM-positive type, Gitschier (1988) found a CGC-to-TGC change in codon 1708 in exon 14, … (more)
In a patient with moderately severe hemophilia A (306700) of a CRM-positive type, Gitschier (1988) found a CGC-to-TGC change in codon 1708 in exon 14, resulting in a change of arginine-1689 to cysteine. The mutation affects the thrombin cleavage site. The same mutation was subsequently found in additional patients (JH38, JH39) by Arai et al. (1990). Aly et al. (1992) found that cysteamine, which is known to modify mutant proteins with an arg-to-cys substitution, enhances the procoagulant activity of the mutant factor VIII, which they referred to as factor VIII-East Hartford. Aly and Hoyer (1992) demonstrated that the East Hartford mutant protein had procoagulant activity when separated from von Willebrand factor; this was taken to indicate that the dissociation of factor VIII from VWF is an essential effect of factor VIII light chain cleavage at arginine-1689. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952184.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. | Johnsen JM | Blood advances | 2017 | PMID: 29296726 |
Computational and molecular approaches for predicting unreported causal missense mutations in Belgian patients with haemophilia A. | Lannoy N | Haemophilia : the official journal of the World Federation of Hemophilia | 2012 | PMID: 21883705 |
Influence of the type of F8 gene mutation on inhibitor development in a single centre cohort of severe haemophilia A patients. | Gouw SC | Haemophilia : the official journal of the World Federation of Hemophilia | 2011 | PMID: 21070499 |
The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. | Margaglione M | Haematologica | 2008 | PMID: 18387975 |
The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients. | David D | Haematologica | 2006 | PMID: 16769589 |
Characterisation of 96 mutations in 128 unrelated severe haemophilia A patients from France. Description of 62 novel mutations. | Vinciguerra C | Thrombosis and haemostasis | 2006 | PMID: 16601827 |
Thirteen novel mutations in the factor VIII gene in the Nijmegen haemophilia A patient population. | Boekhorst J | British journal of haematology | 2005 | PMID: 16173970 |
Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype. | Hill M | Haemophilia : the official journal of the World Federation of Hemophilia | 2005 | PMID: 15810915 |
The identification and classification of 41 novel mutations in the factor VIII gene (F8C). | Cutler JA | Human mutation | 2002 | PMID: 11857744 |
Molecular pathology of haemophilia A in Turkish patients: identification of 36 independent mutations. | Timur AA | Haemophilia : the official journal of the World Federation of Hemophilia | 2001 | PMID: 11554935 |
Lithuanian haemophilia A and B registry comprising phenotypic and genotypic data. | Ivaskevicius V | British journal of haematology | 2001 | PMID: 11298607 |
Start of UK confidential haemophilia A database: analysis of 142 patients by solid phase fluorescent chemical cleavage of mismatch. Haemophilia Centres. | Waseem NH | Thrombosis and haemostasis | 1999 | PMID: 10404764 |
Detection by denaturing gradient gel electrophoresis of an Arg1689Cys mutation in a Chinese patient with mild hemophilia A. | Ruan C | Chinese medical journal | 1997 | PMID: 9594277 |
Factor VIII gene analysis in Japanese CRM-positive and CRM-reduced haemophilia A patients by single-strand conformation polymorphism. | Morichika S | British journal of haematology | 1997 | PMID: 9326186 |
Screening for mutations in haemophilia A patients by multiplex PCR-SSCP, Southern blotting and RNA analysis: the detection of a genetic abnormality in the factor VIII gene in 30 out of 35 patients. | Pieneman WC | British journal of haematology | 1995 | PMID: 7794769 |
Abnormal factor VIII Hiroshima: defect in crucial proteolytic cleavage by thrombin at Arg1689 detected by a novel ELISA. | Kamisue S | British journal of haematology | 1994 | PMID: 8011517 |
Characterization of genetic defects of hemophilia A in patients of Chinese origin. | Lin SW | Genomics | 1993 | PMID: 8307558 |
Factor VIII-East Hartford (arginine 1689 to cysteine) has procoagulant activity when separated from von Willebrand factor. | Aly AM | The Journal of clinical investigation | 1992 | PMID: 1569181 |
Cysteamine enhances the procoagulant activity of Factor VIII-East Hartford, a dysfunctional protein due to a light chain thrombin cleavage site mutation (arginine-1689 to cysteine). | Aly AM | The Journal of clinical investigation | 1992 | PMID: 1569180 |
Detection and characterisation of two missense mutations at a cleavage site in the factor VIII light chain. | Schwaab R | Thrombosis research | 1991 | PMID: 1851341 |
Characterization of mutations in the factor VIII gene by direct sequencing of amplified genomic DNA. | Higuchi M | Genomics | 1990 | PMID: 2105906 |
Characterization of a thrombin cleavage site mutation (Arg 1689 to Cys) in the factor VIII gene of two unrelated patients with cross-reacting material-positive hemophilia A. | Arai M | Blood | 1990 | PMID: 2104766 |
CRM+ haemophilia A due to a missense mutation (372----Cys) at the internal heavy chain thrombin cleavage site. | Pattinson JK | British journal of haematology | 1990 | PMID: 1973901 |
Maternal duplication associated with gene deletion in sporadic hemophilia. | Gitschier J | American journal of human genetics | 1988 | PMID: 2901224 |
Genetic mapping and diagnosis of haemophilia A achieved through a BclI polymorphism in the factor VIII gene. | Gitschier J | Nature | 1985 | PMID: 2986011 |
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Text-mined citations for rs111033613 ...
HelpRecord last updated Oct 08, 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.