ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.599A>G (p.Glu200Gly)
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.599A>G (p.Glu200Gly)
Variation ID: 449370 Accession: VCV000449370.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154992938 (GRCh38) [ NCBI UCSC ] X: 154221213 (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 Dec 19, 2017 Feb 14, 2024 Feb 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000132.4:c.599A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Glu200Gly missense NC_000023.11:g.154992938T>C NC_000023.10:g.154221213T>C NG_011403.2:g.34786A>G LRG_555:g.34786A>G LRG_555t1:c.599A>G LRG_555p1:p.Glu200Gly - Protein change
- E200G
- Other names
- NM_000132.4(F8):c.599A>G
- p.Glu200Gly
- Canonical SPDI
- NC_000023.11:154992937:T:C
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | 1172 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Uncertain significance (1) |
criteria provided, single submitter
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Jul 18, 2019 | RCV000519065.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851605.1 | |
Pathogenic (2) |
reviewed by expert panel
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Feb 2, 2024 | RCV003403227.2 |
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
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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
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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 02, 2024)
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reviewed by expert panel
Method: curation
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Hereditary factor VIII deficiency disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen
Accession: SCV004363677.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
The c.599A>G (p.Glu200Gly) missense variant has a REVEL score of 0.779 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in … (more)
The c.599A>G (p.Glu200Gly) missense variant has a REVEL score of 0.779 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and v3.1 and therefore, does not meet criteria for rarity in the population. At least 9 patients with mild hemophilia A are reported in literature, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID: 29296726, 29388750). Three related individuals were reported in Reitter, et al (PMID: 20431853), and two were specifically mentioned to be uncle and a nephew, which counts as 2 meioses. Additionally, authors of the Boylan, et al. paper informed this VCEP that one of the probands had an affected relative who also has this variant, which is counted as 1 meioses (PMID: 25780857). This gives a total of 3 meioses and meeting PP1_Moderate criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very strong, PP1_Moderate, PP4_Moderate, PP3. (less)
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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: SCV000899356.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1:
Sex: female
Ethnicity/Population group: European
Observation 2:
Sex: male
Ethnicity/Population group: European
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Uncertain significance
(Jul 18, 2019)
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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: SCV000617425.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20431853, 29388750)
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Pathogenic
(Oct 02, 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: SCV004122520.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: F8 c.599A>G (p.Glu200Gly) results in a non-conservative amino acid change in the encoded protein sequence and is located near a consensus splice site. … (more)
Variant summary: F8 c.599A>G (p.Glu200Gly) results in a non-conservative amino acid change in the encoded protein sequence and is located near a consensus splice site. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.5e-06 in 183347 control chromosomes (gnomAD). c.599A>G has been reported in the literature in the hemizygous state in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A) and in the heterozygous state in at least one female individual who had a mild phenotype (e.g. Miller_2012, Debeljak_2012, Eckhardt_2013, Gebhart_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22958177, 31064749, 23926300, 29388750, 22103590). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (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 |
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). | Gebhart J | Haemophilia : the official journal of the World Federation of Hemophilia | 2018 | PMID: 29388750 |
Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. | Eckhardt CL | Blood | 2013 | PMID: 23926300 |
Spectrum of F8 gene mutations in haemophilia A patients from Slovenia. | Debeljak M | Haemophilia : the official journal of the World Federation of Hemophilia | 2012 | PMID: 22958177 |
F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. | Miller CH | Haemophilia : the official journal of the World Federation of Hemophilia | 2012 | PMID: 22103590 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e4caf4f4-de49-400d-96ab-e40e0ec2c926 | - | - | - | - |
Text-mined citations for rs782158761 ...
HelpRecord last updated Feb 28, 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.