Variant summary: F8 c.6545G>A (p.Arg2182His) results in a non-conservative amino acid change located in the coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183342 control chromosomes. c.6545G>A has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (e.g.Miller_2012, Eckhardt_2013, Azadmehr_2021) . These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35014236, 23926300, 22103590). ClinVar contains an entry for this variant (Variation ID: 10320). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.6545G>A (p.Arg2182His)
Germline
Classification
Help
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.
(5)
Help
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000132.4(F8):c.6545G>A (p.Arg2182His)
Variation ID: 10320 Accession: VCV000010320.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154863112 (GRCh38) [ NCBI UCSC ] X: 154091387 (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 Sep 16, 2024 Jun 21, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000132.4:c.6545G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Arg2182His missense NM_019863.3:c.140G>A NP_063916.1:p.Arg47His missense NC_000023.11:g.154863112C>T NC_000023.10:g.154091387C>T NG_011403.2:g.164612G>A LRG_555:g.164612G>A LRG_555t1:c.6545G>A LRG_555p1:p.Arg2182His P00451:p.Arg2182His - Protein change
- R2182H, R47H
- Other names
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F8, ARG2163HIS
R2163H
- Canonical SPDI
- NC_000023.11:154863111: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.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| F8 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
983 | 1259 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 21, 2024 | RCV000011033.16 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jun 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005204121.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: F8 c.6545G>A (p.Arg2182His) results in a non-conservative amino acid change located in the coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein … (more)
Variant summary: F8 c.6545G>A (p.Arg2182His) results in a non-conservative amino acid change located in the coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183342 control chromosomes. c.6545G>A has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (e.g.Miller_2012, Eckhardt_2013, Azadmehr_2021) . These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35014236, 23926300, 22103590). ClinVar contains an entry for this variant (Variation ID: 10320). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(May 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473198.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 08, 2022 |
Comment:
The F8 c.6545G>A; p.Arg2182His variant (rs137852466), also known as p.Arg2163His, is reported in the literature in multiple individuals affected with moderate to severe hemophilia A … (more)
The F8 c.6545G>A; p.Arg2182His variant (rs137852466), also known as p.Arg2163His, is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (see link to Factor VIII database and references therein; Jayandharan 2017, Johnsen 2017, Tuddenham 1994). This variant is reported in ClinVar (Variation ID: 10320), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2182 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.6544C>T; p.Arg2182Cys, c. 6544C>G; p.Arg2182Gly) have been reported in individuals with severe hemophilia A and are considered pathogenic (see link to Factor VIII database, Jayandharan 2009). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII database: http://www.factorviii-db.org Jayandharan GR et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. Tuddenham EG et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucleic Acids Res. 1994 Nov 11;22(22):4851-68. (less)
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Pathogenic
(Sep 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor VIII deficiency disease
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761416.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Jun 01, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary factor VIII deficiency disease
Affected status: yes
Allele origin:
germline
|
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Accession: SCV001424863.1
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
(Jan 01, 1995)
|
no assertion criteria provided
Method: literature only
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HEMOPHILIA A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031260.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Antonarakis et al. (1995) reported this mutation in 2 patients with 5% factor VIII antigen and moderate hemophilia A (306700). The mutation was caused by … (more)
Antonarakis et al. (1995) reported this mutation in 2 patients with 5% factor VIII antigen and moderate hemophilia A (306700). The mutation was caused by a CGC-to-CAC transition at codon 2163 in exon 23 of the C1 domain, resulting in histidine for arginine-2163. (less)
|
Comment:
Comment:
The F8 c.6545G>A; p.Arg2182His variant (rs137852466), also known as p.Arg2163His, is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (see link to Factor VIII database and references therein; Jayandharan 2017, Johnsen 2017, Tuddenham 1994). This variant is reported in ClinVar (Variation ID: 10320), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2182 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.6544C>T; p.Arg2182Cys, c. 6544C>G; p.Arg2182Gly) have been reported in individuals with severe hemophilia A and are considered pathogenic (see link to Factor VIII database, Jayandharan 2009). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII database: http://www.factorviii-db.org Jayandharan GR et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. Tuddenham EG et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucleic Acids Res. 1994 Nov 11;22(22):4851-68.
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. |
Comment:
Variant summary: F8 c.6545G>A (p.Arg2182His) results in a non-conservative amino acid change located in the coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183342 control chromosomes. c.6545G>A has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (e.g.Miller_2012, Eckhardt_2013, Azadmehr_2021) . These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35014236, 23926300, 22103590). ClinVar contains an entry for this variant (Variation ID: 10320). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The F8 c.6545G>A; p.Arg2182His variant (rs137852466), also known as p.Arg2163His, is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (see link to Factor VIII database and references therein; Jayandharan 2017, Johnsen 2017, Tuddenham 1994). This variant is reported in ClinVar (Variation ID: 10320), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2182 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.6544C>T; p.Arg2182Cys, c. 6544C>G; p.Arg2182Gly) have been reported in individuals with severe hemophilia A and are considered pathogenic (see link to Factor VIII database, Jayandharan 2009). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII database: http://www.factorviii-db.org Jayandharan GR et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. Tuddenham EG et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucleic Acids Res. 1994 Nov 11;22(22):4851-68.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The Spectrum of Pathogenic Variants in Iranian Families with Hemophilia A. | Azadmehr S | Archives of Iranian medicine | 2021 | PMID: 35014236 |
| Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. | Eckhardt CL | Blood | 2013 | PMID: 23926300 |
| 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 |
| Independent occurrence of the novel Arg2163 to His mutation in the factor VIII gene in three unrelated families with haemophila A with different phenotypes. Mutations in brief no. 126. Online. | Theophilus BD | Human mutation | 1998 | PMID: 10215414 |
| Molecular etiology of factor VIII deficiency in hemophilia A. | Antonarakis SE | Human mutation | 1995 | PMID: 7728145 |
| Characterization of genetic defects of hemophilia A in patients of Chinese origin. | Lin SW | Genomics | 1993 | PMID: 8307558 |
Text-mined citations for rs137852466 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 27, 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.