VCV000010315.27 - ClinVar

NM_000132.4(F8):c.6506G>A (p.Arg2169His)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

7 out of 9 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000132.4(F8):c.6506G>A (p.Arg2169His)

Variation ID: 10315 Accession: VCV000010315.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154863151 (GRCh38) [ NCBI UCSC ] X: 154091426 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Aug 22, 2016	Jun 29, 2025	Aug 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000132.4:c.6506G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000123.1:p.Arg2169His	missense
NM_019863.3:c.101G>A	NP_063916.1:p.Arg34His	missense
NC_000023.11:g.154863151C>T
NC_000023.10:g.154091426C>T
NG_011403.2:g.164573G>A
LRG_555:g.164573G>A
LRG_555t1:c.6506G>A	LRG_555p1:p.Arg2169His
	P00451:p.Arg2169His

... more HGVS ... less HGVS

Protein change

R2169H, R34H

Other names

F8, ARG2169HIS

Canonical SPDI

NC_000023.11:154863150:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA255208 UniProtKB: P00451#VAR_001187 OMIM: 300841.0231 dbSNP: rs137852461 VarSome

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
Gene	OMIM	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	1089	1371

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.
Hereditary factor VIII deficiency disease	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 14, 2021	RCV000011028.30
Hereditary factor IX deficiency disease	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2019	RCV000851846.10
Hereditary factor VIII deficiency disease Thrombophilia, X-linked, due to factor 8 defect	Pathogenic (1)	criteria provided, single submitter	May 3, 2024	RCV005049328.1
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 13, 2024	RCV003147281.13

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.
Pathogenic (Sep 27, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022269.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary factor VIII deficiency disease Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005416630.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM2_Supporting+PS4+PP4+PP3_Strong

Pathogenic (Aug 13, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885397.6 First in ClinVar: Feb 18, 2019 Last updated: Mar 11, 2025	Comment: The F8 c.6506G>A; p.Arg2169His variant (rs137852461), also known as Arg2150His, is reported in the literature in individuals with mild to moderate hemophilia A (see F8 … (more) The F8 c.6506G>A; p.Arg2169His variant (rs137852461), also known as Arg2150His, is reported in the literature in individuals with mild to moderate hemophilia A (see F8 database and references therein, Bogdanova 2007, Diamond 1992, Green 2008, Higuchi 1991, Suzuki 2018). This variant is reported in ClinVar (Variation ID: 10315) and is absent the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.964). Based on available information, this variant is considered to be pathogenic. References: Link to F8 database: http://www.factorviii-db.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. PMID: 16972227. Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992;1(3):248-57. PMID: 1301932. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. PMID: 18691168. Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405-9. PMID: 1908096. Suzuki et al. Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2, in a Japanese family. Haemophilia. 2018 Jan;24(1):e13-e16. PMID: 29082580. (less)

Pathogenic (May 14, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV002556422.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022

Pathogenic (Jun 20, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005201770.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate a reduction of factor VIII levels and activity in addition to impaired binding to VWF (Jacquemin et al., 2000; van den … (more) Published functional studies demonstrate a reduction of factor VIII levels and activity in addition to impaired binding to VWF (Jacquemin et al., 2000; van den Biggelarr et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R2150H); This variant is associated with the following publications: (PMID: 19473423, 34708896, 35014236, 18691168, 32589464, 21883705, 16972227, 20800587, 19719828, 18387975, 1908096, 29082580, 30046696, 31064749, 18565236, 17610549, 17445092, 17222201, 16769589, 16173970, 12871415, 11857744, 11442643, 11341489, 10910910, 10896236, 10404764, 10338101, 1301932, 33245802, 33706050, 32897612, 15921397, 21909383) (less)

Pathogenic (May 03, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombophilia, X-linked, due to factor 8 defect Hereditary factor VIII deficiency disease Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005683144.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025

Pathogenic (Feb 01, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary factor IX deficiency disease Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899847.2 First in ClinVar: Sep 29, 2019 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 31064749 Zygosity: Hemizygote Sex: male Ethnicity/Population group: East-Asian Platform type: Targeted sequencing

Pathogenic (Jan 01, 1995) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	HEMOPHILIA A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031255.4 First in ClinVar: Apr 04, 2013 Last updated: Jun 29, 2025	Publications: PubMed (6) PubMed: 7728145‚ 1908096‚ 1671991‚ 1301932‚ 1301960‚ 6438527 Comment on evidence: Antonarakis et al. (1995) stated that this mutation had been reported in 10 patients with less than 1 to 7% factor VIII activity and severe … (more) Antonarakis et al. (1995) stated that this mutation had been reported in 10 patients with less than 1 to 7% factor VIII activity and severe to mild hemophilia A (HEMA; 306700). The mutation was caused by a CGT-to-CAT transition at codon 2150 in exon 23 of the C1 domain, resulting in histidine for arginine-2150. The G-to-A transition follows the rule of CG-to-CA mutations at CG dinucleotides. This mutation was reported by Higuchi et al. (1991), Naylor et al. (1993), Diamond et al. (1992); and Jonsdottir et al. (1992). Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated arg2169-to-his (R2169H). (less)

Pathogenic (Jun 01, 2019) N Not contributing to aggregate classification	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: SCV001424858.2 First in ClinVar: Nov 19, 2020 Last updated: Apr 13, 2025	Publications: PubMed (34) PubMed: 1908096‚ 1301932‚ 1301960‚ 19719828‚ 8639447‚ 11857744‚ 16769589‚ 15921397‚ 18387975‚ 10896236‚ 18691168‚ 12871415‚ 9569189‚ 10910910‚ 9829908‚ 18565236‚ 15625837‚ 9326186‚ 20800587‚ 8490618‚ 17445092‚ 17222201‚ 17610549‚ 8584995‚ 8547094‚ 10338101‚ 9452104‚ 11442643‚ 11341489‚ 10404764‚ 16972227‚ 29296726‚ 16173970‚ 21883705 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Causasians

Comment:

The F8 c.6506G>A; p.Arg2169His variant (rs137852461), also known as Arg2150His, is reported in the literature in individuals with mild to moderate hemophilia A (see F8 database and references therein, Bogdanova 2007, Diamond 1992, Green 2008, Higuchi 1991, Suzuki 2018). This variant is reported in ClinVar (Variation ID: 10315) and is absent the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.964). Based on available information, this variant is considered to be pathogenic. References: Link to F8 database: http://www.factorviii-db.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. PMID: 16972227. Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992;1(3):248-57. PMID: 1301932. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. PMID: 18691168. Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405-9. PMID: 1908096. Suzuki et al. Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2, in a Japanese family. Haemophilia. 2018 Jan;24(1):e13-e16. PMID: 29082580.

Comment:

Published functional studies demonstrate a reduction of factor VIII levels and activity in addition to impaired binding to VWF (Jacquemin et al., 2000; van den Biggelarr et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R2150H); This variant is associated with the following publications: (PMID: 19473423, 34708896, 35014236, 18691168, 32589464, 21883705, 16972227, 20800587, 19719828, 18387975, 1908096, 29082580, 30046696, 31064749, 18565236, 17610549, 17445092, 17222201, 16769589, 16173970, 12871415, 11857744, 11442643, 11341489, 10910910, 10896236, 10404764, 10338101, 1301932, 33245802, 33706050, 32897612, 15921397, 21909383)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.	Downes K	Blood	2019	PMID: 31064749
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
Molecular pathology of haemophilia A in Indian patients: identification of 11 novel mutations.	Nair PS	Clinica chimica acta; international journal of clinical chemistry	2010	PMID: 20800587
Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A.	Castaman G	Journal of thrombosis and haemostasis : JTH	2009	PMID: 19719828
Haemophilia A mutations in the UK: results of screening one-third of the population.	Green PM	British journal of haematology	2008	PMID: 18691168
Mutation spectrum of 122 hemophilia A families from Taiwanese population by LD-PCR, DHPLC, multiplex PCR and evaluating the clinical application of HRM.	Lin SY	BMC medical genetics	2008	PMID: 18565236
The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype.	Margaglione M	Haematologica	2008	PMID: 18387975
F8 gene mutation profile and ITT response in a cohort of Italian haemophilia A patients with inhibitors.	Salviato R	Haemophilia : the official journal of the World Federation of Hemophilia	2007	PMID: 17610549
Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development.	Repessé Y	Journal of thrombosis and haemostasis : JTH	2007	PMID: 17445092
In vitro kinetics of factor VIII activity in patients with mild haemophilia A and a discrepancy between one-stage and two-stage factor VIII assay results.	Rodgers SE	British journal of haematology	2007	PMID: 17222201
Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A.	Bogdanova N	Human mutation	2007	PMID: 16972227
The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients.	David D	Haematologica	2006	PMID: 16769589
Thirteen novel mutations in the factor VIII gene in the Nijmegen haemophilia A patient population.	Boekhorst J	British journal of haematology	2005	PMID: 16173970
The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations.	Fernández-López O	Haematologica	2005	PMID: 15921397
Thirty-four novel mutations detected in factor VIII gene by multiplex CSGE: modeling of 13 novel amino acid substitutions.	Habart D	Journal of thrombosis and haemostasis : JTH	2003	PMID: 12871415
The identification and classification of 41 novel mutations in the factor VIII gene (F8C).	Cutler JA	Human mutation	2002	PMID: 11857744
Site and type of mutations in the factor VIII gene in patients and carriers of haemophilia A.	Theophilus BD	Haemophilia : the official journal of the World Federation of Hemophilia	2001	PMID: 11442643
Rapid hemophilia A molecular diagnosis by a simple DNA sequencing procedure: identification of 14 novel mutations.	Vidal F	Thrombosis and haemostasis	2001	PMID: 11341489
A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor.	Jacquemin M	Blood	2000	PMID: 10910910
Relationship between factor VIII mutation type and inhibitor development in a cohort of previously untreated patients treated with recombinant factor VIII (Recombinate). Recombinate PUP Study Group.	Goodeve AC	Thrombosis and haemostasis	2000	PMID: 10896236
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
Screen of 55 Slovenian haemophilia A patients: identification of 2 novel mutations (S-1R and IVS23+1G-->A) and discussion of mutation spectrum. Mutation in brief no. 241. Online.	Strmecki L	Human mutation	1999	PMID: 10338101
Use of denaturing gradient gel blots to screen for point mutations in the factor VIII gene.	Laprise SL	Human mutation	1998	PMID: 9829908
Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation.	Hay CR	Thrombosis and haemostasis	1998	PMID: 9569189
Identification of four novel mutations in the factor VIII gene: three missense mutations (E1875G, G2088S, I2185T) and a 2-bp deletion (1780delTC).	Tavassoli K	Human mutation	1998	PMID: 9452104
[Molecular characterization of genetic defects in hemophilia in Shanghai].	Liu J	Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi	1997	PMID: 15625837
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
Molecular characterization of haemophilia A in southern Chinese.	Chan V	British journal of haematology	1996	PMID: 8639447
Inhibitors to factor VIII in a family with mild hemophilia: molecular characterization and response to factor VIII and desmopressin.	Santagostino E	Thrombosis and haemostasis	1995	PMID: 8584995
Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs.	Schwaab R	British journal of haematology	1995	PMID: 8547094
Molecular etiology of factor VIII deficiency in hemophilia A.	Antonarakis SE	Human mutation	1995	PMID: 7728145
Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients.	Naylor JA	Human molecular genetics	1993	PMID: 8490618
Missense mutations causing mild hemophilia A in Iceland detected by denaturing gradient gel electrophoresis.	Jonsdottir S	Human mutation	1992	PMID: 1301960
Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A.	Diamond C	Human mutation	1992	PMID: 1301932
Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene.	Higuchi M	Proceedings of the National Academy of Sciences of the United States of America	1991	PMID: 1908096
Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene.	Naylor JA	Lancet (London, England)	1991	PMID: 1671991
Structure of human factor VIII.	Vehar GA	Nature	1984	PMID: 6438527
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Text-mined citations for rs137852461 ...

These 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 Jun 29, 2025

ClinVar Genomic variation as it relates to human health

NM_000132.4(F8):c.6506G>A (p.Arg2169His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852461 ...