ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.5123G>A (p.Arg1708His)
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.5123G>A (p.Arg1708His)
Variation ID: 10266 Accession: VCV000010266.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154928667 (GRCh38) [ NCBI UCSC ] X: 154156942 (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 Mar 16, 2024 Dec 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000132.4:c.5123G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Arg1708His missense NC_000023.11:g.154928667C>T NC_000023.10:g.154156942C>T NG_011403.2:g.99057G>A LRG_555:g.99057G>A LRG_555t1:c.5123G>A LRG_555p1:p.Arg1708His P00451:p.Arg1708His - Protein change
- R1708H
- Other names
- F8, ARG1689HIS
- R1689H
- Canonical SPDI
- NC_000023.11:154928666:C:T
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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 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
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
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 |
902 | 1173 |
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
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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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2021 | RCV000010979.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851813.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2022 | RCV001091839.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 20, 2023 | RCV003914826.1 |
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
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
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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
(May 19, 2021)
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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: SCV001804412.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
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: 1064749, … (more)
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: 1064749, 29388750, 27734074, 8485051, 1851341, 19719828, 23020595, 11179760, 24452774, 23711294, 20331761, 21707934, 19473423, 26628308) (less)
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Pathogenic
(Mar 17, 2021)
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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: SCV002050209.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The F8 c.5123G>A; p.Arg1708His variant (rs111033614), also known as p.Arg1689His, is reported in the literature in multiple individuals affected with mild hemophilia A (Gebhart 2018, … (more)
The F8 c.5123G>A; p.Arg1708His variant (rs111033614), also known as p.Arg1689His, is reported in the literature in multiple individuals affected with mild hemophilia A (Gebhart 2018, Schwaab 1995, Factor VIII variant database and references therein), including at least one individual in which it arose de novo (Williams 2012). F8 activity in hemizygous individuals with this variant have been measured between 7%-43% of normal (Factor VIII variant database and references therein). This variant is found on only two chromosomes in the Genome Aggregation Database (2/180265 alleles), 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: 0.885). Additionally, other amino acid substitutions at this codon (p.Arg1708Ser, p.Arg1708Cys, p.Arg1708Leu) have been reported in individuals with hemophilia A and are considered pathogenic (Factor VIII variant database and references therein). Based on available information, the p.Arg1708His variant is considered to be pathogenic. References: Factor VIII variant database: https://f8-db.eahad.org/ 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. Schwaab R et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol. 1995 Oct;91(2):458-64. Williams VK et al. Investigation of inflicted injury in a young girl reveals mild haemophilia A and Turner's syndrome. Int J Lab Hematol. 2012 Feb;34(1):98-101. (less)
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Likely pathogenic
(Jan 18, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003831143.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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F8-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004732490.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The F8 c.5123G>A variant is predicted to result in the amino acid substitution p.Arg1708His. This variant (aka p.Arg1689His) has been reported in multiple individuals with … (more)
The F8 c.5123G>A variant is predicted to result in the amino acid substitution p.Arg1708His. This variant (aka p.Arg1689His) has been reported in multiple individuals with mild hemophilia A or other bleeding disorders (Schwaab et al. 1991. PubMed ID: 1851341; Downes et al. 2019. PubMed ID: 31064749. Suppl3_SNV+INDEL; F8 database: https://www.factorviii-db.org/index.php). Different missense substitution at this same codon (p.Arg1708Cys; p.Arg1708Ser) have also been reported in patients with hemophilia A (Rydz et al. 2013. PubMed ID: 23913812; Lu et al. 2018. PubMed ID: 29381227) suggesting that amino acid residue p.Arg1708 is important for proper F8 protein function. This variant is reported in 0.0055% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. (less)
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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: SCV000899781.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: male
Ethnicity/Population group: European
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Likely pathogenic
(Jul 20, 2021)
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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: SCV002556791.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Mar 01, 1993)
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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: SCV000031206.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Schwaab et al. (1993) found this mutation in 3 patients with 7-11% factor VIII activity, 130-165% factor VIII antigen, and mild hemophilia A (306700). The … (more)
Schwaab et al. (1993) found this mutation in 3 patients with 7-11% factor VIII activity, 130-165% factor VIII antigen, and mild hemophilia A (306700). The mutation is caused by a CGC-to-CAC transition at codon 1689 in exon 14 of the A3 domain, resulting in histidine for arginine-1689. The G-to-A transition follows the rule of CG-to-CA mutations at CG dinucleotides. The mutation has been shown to abolish normal cleavage by thrombin at the light chain. (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
HelpText-mined citations for rs111033614 ...
HelpRecord last updated Mar 17, 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.