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_019863.3:c.347T>C

CA10567758

Gene: F8 (HGNC:2157)

Condition: hemophilia A (MONDO:0010602)

Inheritance Mode: X-linked inheritance

UUID: 0a48c03f-d7c4-45f4-a631-e37c1c45edf2

Approved on: 2026-04-10

Published on: 2026-04-12

HGVS expressions

NM_019863.3:c.347T>C

NC_000023.11:g.154860580A>G

CM000685.2:g.154860580A>G

NC_000023.10:g.154088855A>G

CM000685.1:g.154088855A>G

NC_000023.9:g.153742049A>G

NG_011403.1:g.167144T>C

NG_011403.2:g.167144T>C

ENST00000360256.9:c.6752T>C

ENST00000644698.1:c.485T>C

ENST00000330287.10:c.347T>C

ENST00000360256.8:c.6752T>C

NM_000132.3:c.6752T>C

NM_019863.2:c.347T>C

NM_000132.4:c.6752T>C

Pathogenic

PM2_Supporting PS4_Very Strong PP3

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The NM_000132.4(F8):c.6752T>C (p.Val2251Ala) is a missense variant in F8 that is absent from from gnomAD v4.1.0 meeting PM2_Supporting. The variant is predicted to have a deleterious effect with a REVEL score of 0.953 meeting PP3. The variant has been observed in at least eight probands in the literature and one proband in an internal laboratory cohort with mild to moderate hemophilia A, both with and without inhibitors meeting PS4_Very_Strong (PMID:41071185, 24553597, 23926300, 20331761, 10910913, internal laboratory cohort). In summary, this variant meets the criteria to be classified as pathogenic for hemophilia A. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel specifications version 2.0.0 for F8: PS4_Very_Strong, PM2_Supporting, PP3.

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PS4_Very Strong

This variant has been observed in at least eight probands in the literature and one proband in an internal laboratory cohort with mild to moderate hemophilia A, both with and without inhibitors (PMID:41071185, 3 points PS4; PMID:24553597, 1 point PS4; PMID:23926300, 2 points PS4; PMID:20331761, 1 point PS4; PMID:10910913, 1 point PS4; internal laboratory cohort, 1 point PS4; Total 9 points PS4, PS4_Very_Strong).

PP3

This variant is predicted to have a deleterious effect (REVEL score of 0.953; PP3), which is greater than the Clingen CFD threshold for PP3 (>0.6), with splicing predicted to be unaffected (SpliceAI scores less than 0.1).

Curation History

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