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(F8):c.332C>T (p.Ala111Val)

CA414919986

3380944 (ClinVar)

Gene: F8 (HGNC:2157)

Condition: hemophilia A (MONDO:0010602)

Inheritance Mode: X-linked inheritance

UUID: d3a7e3f1-03d8-45a1-8c07-de0b02e6ff2c

Approved on: 2025-12-05

Published on: 2025-12-05

HGVS expressions

NM_000132.4:c.332C>T

NM_000132.4(F8):c.332C>T (p.Ala111Val)

NC_000023.11:g.154997029G>A

CM000685.2:g.154997029G>A

NC_000023.10:g.154225304G>A

CM000685.1:g.154225304G>A

NC_000023.9:g.153878498G>A

NG_011403.1:g.30695C>T

NG_011403.2:g.30695C>T

ENST00000360256.9:c.332C>T

ENST00000647125.1:c.*118C>T

ENST00000360256.8:c.332C>T

ENST00000423959.5:c.227C>T

ENST00000453950.1:c.314C>T

NM_000132.3:c.332C>T

Uncertain Significance

PS4_Moderate PP3 PM2_Supporting PM5_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.332C>T (p.Ala111Val) 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 0.968), which is greater than the ClinGen CFD threshold for PP3 (>0.6). The variant has been observed in at least two probands with mild to moderate hemophilia A with type 2N von Willebrand disease ruled out (PMID:11857744, External laboratory data; PS4_Moderate). Another missense variant (c.331G>A, p.Ala111Thr, CAID:CA414919991) in the same codon has been classified as likely pathogenic for hemophilia A by the ClinGen Coagulation Factor Deficiency VCEP (PM5_Supporting) with agreement in splicing predictors show no splicing impact. In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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, PM5_Supporting, PM2_Supporting, PP3.

PS4_Moderate

This variant has been observed in at least two probands with mild to moderate hemophilia A with type 2N von Willebrand disease ruled out (PMID:11857744, 1 point PS4; External laboratory data, 1 Point PS4; Total 2 points PS4, PS4_Moderate).

PP3

The c.332C>T (p.Ala111Val) missense variant has a REVEL score of 0.968 (greater than 0.6).

PM2_Supporting

The c.332C>T (p.Ala111Val) variant is from population databases (gnomAD v2.1.1/gnomAD v3).

PM5_Supporting

Another missense variant (c.331G>A, p.Ala111Thr, CAID:CA414919991) in the same codon has been classified as likely pathogenic for hemophilia A by the ClinGen Coagulation Factor Deficiency VCEP (PM5_Supporting) with agreement in splicing predictors show no splicing impact.

Curation History

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