ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.1636C>T (p.Arg546Trp)
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.1636C>T (p.Arg546Trp)
Variation ID: 10222 Accession: VCV000010222.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154957073 (GRCh38) [ NCBI UCSC ] X: 154185348 (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 18, 2023 Feb 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000132.4:c.1636C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Arg546Trp missense NC_000023.11:g.154957073G>A NC_000023.10:g.154185348G>A NG_011403.2:g.70651C>T LRG_555:g.70651C>T LRG_555t1:c.1636C>T LRG_555p1:p.Arg546Trp P00451:p.Arg546Trp - Protein change
- R546W
- Other names
- F8, ARG527TRP
- R527W
- Canonical SPDI
- NC_000023.11:154957072: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.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00009
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
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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 |
891 | 1154 |
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
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 (4) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV000010935.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000852048.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 16, 2022 | RCV003103711.3 |
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
(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: SCV000899541.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: male
Ethnicity/Population group: European
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Pathogenic
(Feb 09, 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:
unknown
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Baylor Genetics
Accession: SCV003835971.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Likely pathogenic
(Dec 04, 2021)
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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:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512663.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 strong, PM2 moderate, PP3 supporting, PP4 supporting
Geographic origin: Brazil
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Pathogenic
(Mar 16, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883824.6
First in ClinVar: Feb 18, 2019 Last updated: Mar 04, 2023 |
Comment:
The F8 c.1636C>T; p.Arg546Trp variant (rs137852416), also known as Arg527Trp, is reported in the literature in individuals with mild to moderate hemophilia A (Bogdanova 2007, … (more)
The F8 c.1636C>T; p.Arg546Trp variant (rs137852416), also known as Arg527Trp, is reported in the literature in individuals with mild to moderate hemophilia A (Bogdanova 2007, Schwaab 1995, Factor VIII database and references therein). This variant is reported in more than 80 affected individuals in the Factor VIII database with clotting activity measurements ranging from 2.3% to 42% of normal. This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 546 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.837). Based on available information, this variant is considered to be pathogenic. References: Factor VIII database: http://f8-db.eahad.org Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. 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. (less)
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Likely pathogenic
(Feb 23, 2023)
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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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3billion
Accession: SCV003841361.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010222 / PMID: 1924291). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Epistaxis (present) , Reduced factor VIII activity (present)
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Pathogenic
(Jan 01, 1995)
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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: SCV000031162.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Higuchi et al. (1991) found this mutation in a patient with 9.5-38% factor VIII activity, 43-245% factor VIII antigen, and mild hemophilia A (306700). The … (more)
Higuchi et al. (1991) found this mutation in a patient with 9.5-38% factor VIII activity, 43-245% factor VIII antigen, and mild hemophilia A (306700). The mutation is caused by a CGG-to-TGG transition at codon 527 in exon 11 of the A2 domain, resulting in tryptophan for arginine-527. The C-to-T transition follows the rule of CG-to-TG mutations at CG dinucleotides. This mutation has also been found by others (McGinniss et al., 1993; see also Antonarakis et al., 1995). (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 |
Molecular etiology of factor VIII deficiency in hemophilia A. | Antonarakis SE | Human mutation | 1995 | PMID: 7728145 |
Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A. | McGinniss MJ | Genomics | 1993 | PMID: 8449505 |
Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. | Higuchi M | Proceedings of the National Academy of Sciences of the United States of America | 1991 | PMID: 1924291 |
Text-mined citations for rs137852416 ...
HelpRecord last updated Mar 26, 2023
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.