VCV000010318.14 - ClinVar

NM_000132.4(F8):c.6532C>T (p.Arg2178Cys)

Germline

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.

(6)

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/Likely pathogenic

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.6532C>T (p.Arg2178Cys)

Variation ID: 10318 Accession: VCV000010318.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154863125 (GRCh38) [ NCBI UCSC ] X: 154091400 (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	Nov 18, 2015	Nov 24, 2024	Apr 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000132.4:c.6532C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000123.1:p.Arg2178Cys	missense
NM_019863.3:c.127C>T	NP_063916.1:p.Arg43Cys	missense
NC_000023.11:g.154863125G>A
NC_000023.10:g.154091400G>A
NG_011403.2:g.164599C>T
LRG_555:g.164599C>T
LRG_555t1:c.6532C>T	LRG_555p1:p.Arg2178Cys
	P00451:p.Arg2178Cys

... more HGVS ... less HGVS

Protein change

R2178C, R43C

Other names

F8, ARG2159CYS
R2159C

Canonical SPDI

NC_000023.11:154863124:G:A

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

Trans-Omics for Precision Medicine (TOPMed) 0.00008

Links

ClinGen: CA255211 UniProtKB: P00451#VAR_001190 OMIM: 300841.0234 dbSNP: rs137852464 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	984	1260

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	Mar 10, 2023	RCV000011031.17
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 10, 2024	RCV003103985.3

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 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 (Jun 13, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049465.3 First in ClinVar: Jan 08, 2022 Last updated: Mar 04, 2023	Comment: The F8 c.6532C>T; p.Arg2178Cys variant (rs137852464), also known as R2159C, is reported in the literature in multiple individuals and families affected with mild to moderate … (more) The F8 c.6532C>T; p.Arg2178Cys variant (rs137852464), also known as R2159C, is reported in the literature in multiple individuals and families affected with mild to moderate hemophilia A (see link to FVIII database and references therein, Markoff 2009). This variant is also reported in ClinVar (Variation ID: 10318). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2178 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.875). Additionally, other amino acid substitutions at this codon (Leu, His, Lys) have been reported in individuals with mild hemophilia A and are considered pathogenic (FVIII database, Markoff 2009). Based on available information, the p.Arg2178Cys variant is considered to be pathogenic. References: Link to FVIII database: http://www.factorviii-db.org/ Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. PMID: 19473423 (less)
Pathogenic (Oct 27, 2021)	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: SCV004175453.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023
Pathogenic (Mar 10, 2023)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Hereditary factor VIII deficiency disease Affected status: unknown Allele origin: inherited	New York Genome Center Study: PrenatalSEQ Accession: SCV005044080.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Publications: PubMed (4) PubMed: 1924291‚ 11754115‚ 17445092‚ 21771207 Comment: The hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant (also called R2159C, or p.Arg2159Cys) identified in the F8 gene of this fetus has been reported in many … (more) The hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant (also called R2159C, or p.Arg2159Cys) identified in the F8 gene of this fetus has been reported in many affected individuals and is typically associated with mild hemophilia A [PMID:1924291, 11754115, 17445092, 21771207, others]. Decreased Factor VIII activity has been reported in a male with the c.6532C>T, p.(Arg2178Cys) variant [PMID:1924291]. This variant is reported in ClinVar as Pathogenic (VarID:10318; 1 star, 3 submissions, no conflicts), and two different amino acid changes at the same amino acid position, p.Arg2178Leu (VarID:10314) and p.Arg2178His (VarID:10319) are also reported as Likely Pathogenic/Pathogenic. In silico algorithm REVEL predicts this variant to be damaging to protein function (Score: 0.875). Given the available evidence the hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant identified in the F8 gene is reported as Pathogenic. (less) Clinical Features: Short long bone (present) , Hypospadias (present) Zygosity: Hemizygote Age: 30-39 weeks gestation Secondary finding: yes
Likely pathogenic (Apr 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413463.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (13) PubMed: 10910913‚ 1301960‚ 18400180‚ 1923751‚ 1924291‚ 19473423‚ 23926300‚ 25824987‚ 32166871‚ 33706050‚ 37937776‚ 38196513‚ 8449505 Comment: PP1, PP3, PM1, PM2_moderate, PM5, PS4_moderate Number of individuals with the variant: 2
Pathogenic (Jan 01, 1995)	no assertion criteria provided Method: literature only	HEMOPHILIA A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031258.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 18, 2015	Publications: PubMed (5) PubMed: 7728145‚ 1924291‚ 8449505‚ 1301932‚ 1301960 Comment on evidence: Antonarakis et al. (1995) stated that this mutation had been reported in 12 patients with 6 to 26% factor VIII activity, less than 5 to … (more) Antonarakis et al. (1995) stated that this mutation had been reported in 12 patients with 6 to 26% factor VIII activity, less than 5 to 15.7% factor VIII antigen, and mild hemophilia A (306700). The mutation was caused by a CGC-to-TGC transition at codon 2159 in exon 23 of the C1 domain, resulting in cysteine for arginine-2159. The mutation was reported by Higuchi et al. (1991), McGinniss et al. (1993); Diamond et al. (1992); and Jonsdottir et al. (1992). (less)
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: SCV001424874.1 First in ClinVar: Nov 19, 2020 Last updated: Nov 19, 2020	Publications: PubMed (25) PubMed: 7579394‚ 11748850‚ 19719828‚ 11857744‚ 16769589‚ 1301932‚ 18691168‚ 12871415‚ 1908096‚ 16128892‚ 1301960‚ 21462120‚ 17610560‚ 18565236‚ 8449505‚ 8490618‚ 17445092‚ 20102490‚ 8547094‚ 9184393‚ 11554935‚ 10404764‚ 29296726‚ 16173970‚ 21883705 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Causasians

Comment:

The F8 c.6532C>T; p.Arg2178Cys variant (rs137852464), also known as R2159C, is reported in the literature in multiple individuals and families affected with mild to moderate hemophilia A (see link to FVIII database and references therein, Markoff 2009). This variant is also reported in ClinVar (Variation ID: 10318). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2178 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.875). Additionally, other amino acid substitutions at this codon (Leu, His, Lys) have been reported in individuals with mild hemophilia A and are considered pathogenic (FVIII database, Markoff 2009). Based on available information, the p.Arg2178Cys variant is considered to be pathogenic. References: Link to FVIII database: http://www.factorviii-db.org/ Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. PMID: 19473423

Comment:

The hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant (also called R2159C, or p.Arg2159Cys) identified in the F8 gene of this fetus has been reported in many affected individuals and is typically associated with mild hemophilia A [PMID:1924291, 11754115, 17445092, 21771207, others]. Decreased Factor VIII activity has been reported in a male with the c.6532C>T, p.(Arg2178Cys) variant [PMID:1924291]. This variant is reported in ClinVar as Pathogenic (VarID:10318; 1 star, 3 submissions, no conflicts), and two different amino acid changes at the same amino acid position, p.Arg2178Leu (VarID:10314) and p.Arg2178His (VarID:10319) are also reported as Likely Pathogenic/Pathogenic. In silico algorithm REVEL predicts this variant to be damaging to protein function (Score: 0.875). Given the available evidence the hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant identified in the F8 gene is reported as Pathogenic.

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
Variant spectrum of F8 and F9 in hemophilia patients from southern China and 26 novel variants.	Li F	Frontiers in genetics	2023	PMID: 38196513
Actionable Genotypes and Their Association with Life Span in Iceland.	Jensson BO	The New England journal of medicine	2023	PMID: 37937776
The spectrum of FVIII gene variants detected by next generation sequencing in 236 Chinese non-inversion hemophilia A pedigrees.	Chen J	Thrombosis research	2021	PMID: 33706050
The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers.	McVey JH	Haemophilia : the official journal of the World Federation of Hemophilia	2020	PMID: 32166871
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
Overrepresentation of missense mutations in mild hemophilia A patients from Belgium: founder effect or independent occurrence?	Lannoy N	Thrombosis research	2015	PMID: 25824987
Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.	Eckhardt CL	Blood	2013	PMID: 23926300
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
The natural history of mild haemophilia: a 30-year single centre experience.	Tagliaferri A	Haemophilia : the official journal of the World Federation of Hemophilia	2012	PMID: 21771207
[Mutation screening of the F VIII gene in 10 hemophilia A families].	LI W	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2011	PMID: 21462120
Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile.	Santagostino E	Journal of thrombosis and haemostasis : JTH	2010	PMID: 20102490
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
Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function.	Markoff A	Haemophilia : the official journal of the World Federation of Hemophilia	2009	PMID: 19473423
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
Crystal structure of human factor VIII: implications for the formation of the factor IXa-factor VIIIa complex.	Ngo JC	Structure (London, England : 1993)	2008	PMID: 18400180
The molecular aetiology of haemophilia A in a New Zealand patient group.	Laurie AD	Haemophilia : the official journal of the World Federation of Hemophilia	2007	PMID: 17610560
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
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
Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions.	Jayandharan G	Haemophilia : the official journal of the World Federation of Hemophilia	2005	PMID: 16128892
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
Seven novel and four recurrent point mutations in the factor VIII (F8C) gene.	Bogdanova N	Human mutation	2002	PMID: 11754115
Seven novel and four recurrent point mutations in the factor VIII (F8C) gene.	Bogdanova N	Human mutation	2001	PMID: 11748850
Molecular pathology of haemophilia A in Turkish patients: identification of 36 independent mutations.	Timur AA	Haemophilia : the official journal of the World Federation of Hemophilia	2001	PMID: 11554935
Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure.	Liu ML	Blood	2000	PMID: 10910913
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
Factor VIII Ise (R2159C) in a patient with mild hemophilia A, an abnormal factor VIII with retention of function but modification of C2 epitopes.	Suzuki H	Thrombosis and haemostasis	1997	PMID: 9184393
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
Eleven novel mutations in the factor VIII gene from Brazilian hemophilia A patients.	Arruda VR	Blood	1995	PMID: 7579394
Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients.	Naylor JA	Human molecular genetics	1993	PMID: 8490618
Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A.	McGinniss MJ	Genomics	1993	PMID: 8449505
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 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
Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene.	Tuddenham EG	Nucleic acids research	1991	PMID: 1923751
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
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Text-mined citations for rs137852464 ...

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 Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000132.4(F8):c.6532C>T (p.Arg2178Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852464 ...