chrX-154904998-C-T

Position:

• chrX-154904998-C-T

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3 PP4_Moderate PS4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000132.4(F8):c.5399G>A (p.Arg1800His) variant is completely absent from gnomAD v2.1.1 and gnomAD v3.1.2, meeting the PM2_Supporting criteria. More than 17 individuals in the literature and 40 in the internal laboratory data are observed with hemophilia A ranging from mild to severe carrying the Arg1800His variant. More cases are available in the literature (EAHAD database reports 76 individuals); however, the threshold for PS4_VeryStrong (>8) and PP4_Moderate have been reached. This variant has been associated with discrepant factor VIII activity levels (PMID:32232366). This variant has also been associated with inhibitor development to factor replacement therapy (CDC CHAMPS/EAHAD databases). The c.5399G>A (p.Arg1800His) missense variant has a REVEL score of 0.96 (>0.6), which meets the PP3 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_VeryStrong, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255162/MONDO:0010602/071

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: F8 ENST00000360256.9 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 7.46

Genes affected

F8 (HGNC:3546): (coagulation factor VIII) This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.5399G>A	p.Arg1800His	missense_variant	16/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.5399G>A	p.Arg1800His	missense_variant	16/26	1	NM_000132.4	ENSP00000353393	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092707 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 358351

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 19, 2023	PP3, PP4, PP5, PM2_moderate, PS4_moderate -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2019	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies suggest a damaging effect; Presence of R1800H (reported as R1781H) resulted in a relative enhancement in association between FVIIIa and FX (Yada et al., 2013); This variant is associated with the following publications: (PMID: 33245802, 30507053, 23467620, 19817879, 27292088, 19473423, 1908096) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary factor VIII deficiency disease Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 02, 2024	The NM_000132.4(F8):c.5399G>A (p.Arg1800His) variant is completely absent from gnomAD v2.1.1 and gnomAD v3.1.2, meeting the PM2_Supporting criteria. More than 17 individuals in the literature and 40 in the internal laboratory data are observed with hemophilia A ranging from mild to severe carrying the Arg1800His variant. More cases are available in the literature (EAHAD database reports 76 individuals); however, the threshold for PS4_VeryStrong (>8) and PP4_Moderate have been reached. This variant has been associated with discrepant factor VIII activity levels (PMID: 32232366). This variant has also been associated with inhibitor development to factor replacement therapy (CDC CHAMPS/EAHAD databases). The c.5399G>A (p.Arg1800His) missense variant has a REVEL score of 0.96 (>0.6), which meets the PP3 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_VeryStrong, PP4_Moderate, PP3, PM2_Supporting. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 13, 2019	The F8 c.5399G>A; p.Arg1800His variant (rs137852442), also known as p.Arg1781His using alternative nomenclature, has been reported in multiple patients with moderate to severe hemophilia A (Casana 2008, Higuchi 1991, Yada 2013, Factor VIII variant database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 1800 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. These predictions are consistent with activity measurements of patient samples with this variant, which exhibit 1-10% of normal clotting activity (Factor VIII variant database). Additionally, other amino acid substitutions at this codon (Cys, Gly, Leu, and Pro) have been reported in individuals with hemophilia A and are considered disease-causing (Factor VIII variant database). Based on available information, the p.Arg1800His variant is classified as pathogenic. References: Factor VIII variant database: http://www.factorviii-db.org/newstructure.php?aa_first=Arg&mut_id=1263&aa_last=His Casana P et al. Severe and moderate hemophilia A: identification of 38 new genetic alterations. Haematologica. 2008 Jul;93(7):1091-4. 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; 88(16):7405-9. Yada K et al. The mild phenotype in severe hemophilia A with Arg1781His mutation is associated with enhanced binding affinity of factor VIII for factor X. Thromb Haemost. 2013; 109(6):1007-15. -

F8-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2022

The F8 c.5399G>A variant is predicted to result in the amino acid substitution p.Arg1800His. This variant, also described using legacy nomenclature as p.Arg1781His, has been reported in individuals with moderate to severe Hemophilia A (Higuchi et al. 1991. PubMed ID: 1908096; Casaña et al. 2008. PubMed ID: 18403393; Yada et al. 2013. PubMed ID: 23467620; Kars et al. 2021. PubMed ID: 34426522. Dataset S4; Factor VIII variant database: https://f8-db.eahad.org/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.96
Sift	Benign	0.037	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.89		Loss of phosphorylation at S1803 (P = 0.0616);
MVP		0.99
MPC		0.35
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.61		Position offset: 25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852442; hg19: chrX-154133273; COSMIC: COSV100811547; COSMIC: COSV100811547;