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]

Variant: NM_000133.4(F9):c.802T>A (p.Cys268Ser)

CA414443531

627143 (ClinVar)

Gene: F9 (HGNC:2158)

Condition: hemophilia B (MONDO:0010604)

Inheritance Mode: X-linked inheritance

UUID: 27098047-1cd6-476e-980b-90322be70d28

Approved on: 2024-12-06

Published on: 2024-12-06

HGVS expressions

NM_000133.4(F9):c.802T>A (p.Cys268Ser)

NM_000133.4:c.802T>A

NC_000023.11:g.139560819T>A

CM000685.2:g.139560819T>A

NC_000023.10:g.138642978T>A

CM000685.1:g.138642978T>A

NC_000023.9:g.138470644T>A

NG_007994.1:g.35084T>A

ENST00000218099.7:c.802T>A

ENST00000643157.1:n.1469T>A

ENST00000218099.6:c.802T>A

ENST00000394090.2:c.688T>A

NM_000133.3:c.802T>A

NM_001313913.1:c.688T>A

NM_001313913.2:c.688T>A

Likely Pathogenic

PP4_Moderate PS4_Moderate PP3 PM2_Supporting PM5

PM1

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 F9 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The F9 c.802T>A (p.Cys268Ser) variant is completely absent from gnomAD v2.1.1 and v3.1.1 meeting PM2_Supporting. This missense variant has a REVEL score of 0.969 and meets PP3 criteria (threshold >0.6 - PP3). Three probands are reported in the literature with moderate and severe hemophilia B meeting F9 criteria (PMID: 31064749, PMID: 8091381, PMID: 21263151 - PS4_Moderate & PP4_Moderate). The c.802T>A (p.Cys268Ser) variant is a missense change at the same residue (p.Cys268) where at least 3 different missense changes have been previously established as pathogenic/likely pathogenic variants (p.Cys268Gly, p.Cys268Arg, p.Cys268Tyr) using CFD-VCEP rules for F9 and SpliceAI shows no splicing impact (PM5). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Moderate, PP4_Moderate, PM5, PM2_Supporting, PP3.

PP4_Moderate

PMID: 31064749: Proband with hemophilia B from the ThromboGenomics cohort.

PS4_Moderate

2 probands with hemophilia B reported in literature counted for PS4. PMID: 8091381, PMID: 21263151. Note, the third proband in the literature from PMID: 31064749 is counted under PP4_Moderate.

PP3

REVEL score is 0.969, which is above the 0.6 cutoff.

PM2_Supporting

Variant is absent in gnomAD v2.1.1 or v3.1.

PM5

The c.5186G>A (p.Gly1729Glu) variant is a missense change at the same residue (p.1729) where at least 3 different missense changes have been previously established as pathogenic/likely pathogenic variants using CFD-VCEP rules for F8/F9 and RNA data or agreement in splicing predictors (SpliceAI <0.01) show no splicing impact.

PM1

Variant is not within exons 4, 5 or 6.

Curation History

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.