Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000132.4(F8):c.5399G>A (p.Arg1800His)

CA255162

10274 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 1098415e-d0dd-480c-8171-d26c81d47a2b

Approved on: 2024-02-02

Published on: 2024-07-11

HGVS expressions

NM_000132.4:c.5399G>A

NM_000132.4(F8):c.5399G>A (p.Arg1800His)

NC_000023.11:g.154904998C>T

CM000685.2:g.154904998C>T

NC_000023.10:g.154133273C>T

CM000685.1:g.154133273C>T

NC_000023.9:g.153786467C>T

NG_011403.1:g.122726G>A

NG_011403.2:g.122726G>A

ENST00000360256.9:c.5399G>A

ENST00000360256.8:c.5399G>A

NM_000132.3:c.5399G>A

Pathogenic

PS4 PP3 PP4_Moderate PM2_Supporting

Evidence Links 0

Expert Panel

Coagulation Factor Deficiency VCEP

Criteria Specification Information

Criteria Specification: ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

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.

PS4

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) has been reached.

PP3

The c.5399G>A (p.Arg1800His) missense variant has a REVEL score of 0.96 (>0.6)

PP4_Moderate

Male with severe hemophilia A who had full F8 and F9 gene sequencing and deletion/duplication analysis through the MLOF study.

PM2_Supporting

The c.5399G>A (p.Arg1800His) variant is completely absent from gnomAD v2.1.1 and gnomAD v3.1.2

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.