NM_000132.4(F8):c.6371A>G (p.Tyr2124Cys) AND Hereditary factor VIII deficiency disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Apr 3, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000011023.23

Allele description [Variation Report for NM_000132.4(F8):c.6371A>G (p.Tyr2124Cys)]

NM_000132.4(F8):c.6371A>G (p.Tyr2124Cys)

Gene:

F8:coagulation factor VIII [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000132.4(F8):c.6371A>G (p.Tyr2124Cys)

Other names:

F8, TYR2124CYS

HGVS:

NC_000023.11:g.154896135T>C
NG_011403.2:g.131589A>G
NM_000132.4:c.6371A>GMANE SELECT
NP_000123.1:p.Tyr2124Cys
NP_000123.1:p.Tyr2124Cys
NP_000123.1:p.Tyr2124Cys
LRG_555t1:c.6371A>G
LRG_555:g.131589A>G
LRG_555p1:p.Tyr2124Cys
NC_000023.10:g.154124410T>C
NG_011403.1:g.131589A>G
NM_000132.3:c.6371A>G
P00451:p.Tyr2124Cys

Protein change:

Y2124C; TYR2124CYS

Links:

UniProtKB: P00451#VAR_001183; OMIM: 300841.0227; dbSNP: rs137852459

NCBI 1000 Genomes Browser:

rs137852459

Molecular consequence:

NM_000132.4:c.6371A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary factor VIII deficiency disease (HEMA)
Synonyms:: AUTOSOMAL HEMOPHILIA A; Hemophilia A; Hemophilia A, congenital; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010602; MedGen: C0019069; Orphanet: 98878; OMIM: 306700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000031250	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1993)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8281136, 6438527
SCV002048196	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (May 3, 2021)	germline	clinical testing	Citation Link,
SCV004175323	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10910913, 25741868
SCV005075822	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 3, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23926300, 22103590 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions.

Naylor J, Brinke A, Hassock S, Green PM, Giannelli F.

Hum Mol Genet. 1993 Nov;2(11):1773-8.

PubMed [citation]

PMID:: 8281136

Structure of human factor VIII.

Vehar GA, Keyt B, Eaton D, Rodriguez H, O'Brien DP, Rotblat F, Oppermann H, Keck R, Wood WI, Harkins RN, Tuddenham EG, Lawn RM, Capon DJ.

Nature. 1984 Nov 22-28;312(5992):337-42.

PubMed [citation]

PMID:: 6438527

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000031250.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

Naylor et al. (1993) found this mutation in a patient with 14% factor VIII activity and mild hemophilia A (306700). The mutation was caused by a TAT-to-TGT transition at codon 2105 in exon 22 of the C1 domain, resulting in cysteine for tyrosine-2105. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated tyr2124-to-cys (Y2124C).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048196.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The F8 6371A>G; p.Tyr2124Cys variant (rs137852459), also known as Tyr2105Cys, has been described in the literature in numerous individuals with mild/moderate hemophilia A (Naylor 1993, Margaglione 2008, Johnsen 2017, Williams 2015, F8 database), and it is also reported in ClinVar (Variation ID: 10310). This variant is only observed on one allele (one hemizygote) in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 2124 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.97). Taken together, this variant is considered pathogenic. References: Naylor JA et al. Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients. Hum Mol Genet. 1993 Jan;2(1):11-7. PMID: 8490618 Margaglione M et al. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008 May;93(5):722-8. PMID: 18387975 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. PMID: 29296726 Williams VK et al. Extensive bleeding due to an inhibitor in a haemophilia A patient with a Tyr2105Cys mutation: elimination of the inhibitor with rituximab. Pathology. 2015 Oct;47(6):586-8. PMID: 26308136 Link to F8 database: https://f8-db.eahad.org/VariantPage.php?ID=1594&hash=2a3f84a96bdd139de9f11adfe4865fbc

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV004175323.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The F8 c.6371A>G variant is classified as Likely Pathogenic (PS4_Moderate, PM1, PM2, PP3) The F8 c.6371A>G variant is a single nucleotide change in exon 22/26 of the F8 gene, which is predicted to change the amino acid tyrosine at position 2124 in the protein to cysteine. The variant has been reported in numerous individuals with a clinical presentation of mild to severe haemophilia as reported in the EAHAD F8 Variant database (PS4_Mod). Note that this variant is also reported in the literature as Tyr2105Cys.This variant is absent from population databases (PM2). This variant is located in the Factor VIII C domain which contains key binding sites for von Willebrand factor (vWF) and phospholipid membranes (PMID: 10910913) (PM1). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs137852459) and in the HGMD database: CM930235. It has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 10310).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005075822.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: F8 c.6371A>G (p.Tyr2124Cys) 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 allele was found at a frequency of 5.5e-06 in 183296 control chromosomes. c.6371A>G has been reported in the literature in multiple individuals affected with milder/non-severe Factor VIII Deficiency (Hemophilia A). 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: 23926300, 22103590). ClinVar contains an entry for this variant (Variation ID: 10310). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 7, 2024

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