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]

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Variant: NM_000133.3(F9):c.880C>T (p.Arg294Ter)

CA255344

10587 (ClinVar)

Gene: F9

Condition: hemophilia B

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 0742efeb-756a-4f9c-9d90-b29a1c2a1c24

Approved on: 2024-02-09

Published on: 2024-07-11

HGVS expressions

NM_000133.3:c.880C>T

NM_000133.3(F9):c.880C>T (p.Arg294Ter)

NC_000023.11:g.139561565C>T

CM000685.2:g.139561565C>T

NC_000023.10:g.138643724C>T

CM000685.1:g.138643724C>T

NC_000023.9:g.138471390C>T

NG_007994.1:g.35830C>T

ENST00000218099.7:c.880C>T

ENST00000643157.1:n.1547C>T

ENST00000218099.6:c.880C>T

ENST00000394090.2:c.766C>T

NM_001313913.1:c.766C>T

NM_000133.4:c.880C>T

NM_001313913.2:c.766C>T

Pathogenic

PS4 PP4_Moderate PM2_Supporting PVS1_Strong

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.880C>T (Arg294Ter) variant occurs in exon 8/8 of the F9 gene, and NMD is not predicted. PVS1_Strong is applied based on truncation of the Peptidase S1 domain. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, meeting PM2_Supporting criteria. Over 90 patients have been reported in the literature and the EAHAD database with hemophilia B in the moderate-severe range and history of inhibitors to factor replacement products are reported, meeting PP4_Moderate and PS4_Very strong (selected PMIDs: 29296726, 8217825, 8314564). 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 F9: PS4_VeryStrong, PVS1_Strong, PP4_Moderate, PM2_Supporting.

PS4

At least 39 patients are counted from the literature and internal laboratory data with the Arg294Ter variant and hemophilia B in the moderate-severe range. Several other probands are in the literature and EAHAD database reports 92 patients. However, the threshold for PS4_Very Strong (>8 probands) has been reached.

PP4_Moderate

Male with severe hemophilia B with an inhibitor to factor replacement product. All participants in MLOF project had F8 and F9 full gene sequencing and deletion/duplication analysis.

PM2_Supporting

The c.880C>T (p.Arg294Ter) variant is completely absent from gnomAD v2.1.1 and v3.1.1

PVS1_Strong

The c.880C>T (Arg294Ter) variant occurs in exon 8/8 of the F9 gene, and NMD is not predicted. PVS1_Strong is applied based on truncation of the Peptidase S1 domain.

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