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_000132.4:c.331G>A

CA414919991

Gene: F8 (HGNC:2157)

Condition: hemophilia A (MONDO:0010602)

Inheritance Mode: X-linked inheritance

UUID: b6022722-3f46-4630-987c-eb19e98c170b

Approved on: 2025-12-05

Published on: 2025-12-05

HGVS expressions

NM_000132.4:c.331G>A

NC_000023.11:g.154997030C>T

CM000685.2:g.154997030C>T

NC_000023.10:g.154225305C>T

CM000685.1:g.154225305C>T

NC_000023.9:g.153878499C>T

NG_011403.1:g.30694G>A

NG_011403.2:g.30694G>A

ENST00000360256.9:c.331G>A

ENST00000647125.1:c.*117G>A

ENST00000360256.8:c.331G>A

ENST00000423959.5:c.226G>A

ENST00000453950.1:c.313G>A

NM_000132.3:c.331G>A

Likely Pathogenic

PP3 PS4_Moderate PM2_Supporting PP4_Moderate

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.331G>A (p.Ala111Thr) variant is a missense variant in F8 that is absent from population databases (gnomAD v2.1.1/gnomAD v3; PM2_Supporting) and is predicted to have a deleterious effect (REVEL score of 0.966), which is greater than the ClinGen CFD threshold for PP3 (>0.6; PP3). This variant has been observed in at least four probands in the literature with moderate to severe hemophilia A, both with and without the development of F8 inhibitors (PMID:25628142, PMID:15682412, PMID:33254277, PS4_Moderate; PMID:29296726, PP4_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for hemophilia A. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel (specifications version 1.0.0) for F8: PS4_Moderate, PP4_Moderate, PM2_Supporting, PP3.

PP3

This variant is predicted to have a deleterious effect (REVEL score of 0.966; PP3), which is greater than the Clingen CFD threshold for PP3 (>0.6).

PS4_Moderate

This variant has been observed in multiple patients in the literature with moderate to severe hemophilia A, both with and without the development of F8 inhibitors (1 point, PMID:25628142; 1 point, PMID:15682412; 1 point, PMID:33254277; Total: 3 points PS4; PS4_Moderate).

PM2_Supporting

This variant is absent from population databases (gnomAD v2.1.1/gnomAD v3; PM2_Supporting).

PP4_Moderate

There is at least 1 proband with moderate hemophilia A with a F8 inhibitor, meeting phenotypic criteria for F8 (PP4_Moderate, PMID:29296726).

Curation History

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