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_000133.3(F9):c.88G>C (p.Val30Leu)

CA414434503

627400 (ClinVar)

Gene: F9 (HGNC:2158)

Condition: hemophilia B (MONDO:0010604)

Inheritance Mode: X-linked inheritance

UUID: 3b97275b-1610-4c8c-aa33-afd4f5c09395

Approved on: 2026-04-10

Published on: 2026-04-12

HGVS expressions

NM_000133.3(F9):c.88G>C (p.Val30Leu)

NM_000133.3:c.88G>C

NC_000023.11:g.139530852G>C

CM000685.2:g.139530852G>C

NC_000023.10:g.138613011G>C

CM000685.1:g.138613011G>C

NC_000023.9:g.138440677G>C

NG_007994.1:g.5117G>C

ENST00000218099.7:c.88G>C

ENST00000218099.6:c.88G>C

ENST00000394090.2:c.88G>C

ENST00000479617.2:n.95G>C

NM_001313913.1:c.88G>C

NM_000133.4:c.88G>C

NM_001313913.2:c.88G>C

Likely Pathogenic

PS3_Supporting PS1_Moderate PP3 PS4_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 F9 Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The F9 c.88G>C, p.Val30Leu variant is completely absent from gnomAD v4.1.0 meeting PM2_Supporting. The computational splicing predictor SpliceAI gives a score of 0.97 for donor loss, predicting that the variant disrupts the donor splice site of intron 1 of F9 meeting PP3. Additionally, the c.88G>A, p.Val30Ile variant is also predicted to impact splicing (SpliceAI donor loss score of 0.96) and was previously classified as a likely pathogenic variant using the CFD VCEP rule specifications, meeting PS1_Moderate. Two probands with the Val30Leu variant have been reported with moderate or severe hemophilia B meeting PS4_Moderate (PMID: 31064749, EAHAD Factor IX (F9) Database). Secreted conformation-specific reporter (SCSR) assay in HEK293T cells showed decreased SCSR levels compared to that of the WT, indicating that this variant impacts protein function (PMID: 32766856; PS3_Supporting). In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 v2.0.0: PS1_Moderate, PS4_Moderate, PP3, PM2_Supporting, PS3_Supporting.

PS3_Supporting

PMID: 32766856 analyzed variants in a cell-based reporter assay with levels of secreted conformation-specific reporter with a functional γ-carboxyglutamate (Gla) domain of FIX. The Val30Leu variant showed less secretion of functional protein. The actual levels of FIX:C and FIX:Ag are not available; however, since this assay has been accepted as valid by the CFD VCEP, PS3_Supporting criteria is met.

PS1_Moderate

Val30Ile is a variant at the same residue and is classified as likely pathogenic by the CFD-VCEP yet. Both Val30Leu and Val30Ile are predicted to impact splicing. The computational splicing predictor SpliceAI gives a score of 0.97 for donor loss, predicting that the variant disrupts the donor splice site of intron 1 of F9. For the F9 c.88G>A, p.Val30Ile variant, the computational splicing predictor SpliceAI gives a score of 0.96 for donor loss.

PP3

The c.88G>C (p.Val30Leu) missense variant has a REVEL score of 0.787 (>0.6). The variant affects the last codon of exon 1 and spliceAI predicts a splicing impact with delta score of 0.97.

PS4_Moderate

1 proband with the Val30Leu variant and moderate hemophilia B is reported in the literature (PMID: 31064749) and 1 proband with severe hemophilia B is listed in the EAHAD factor IX (F9) database.

PM2_Supporting

The c.88G>C; p.Val30Leu variant is completely absent from gnomAD v4.1.1.

Curation History

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