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_000132.3:c.1420G>T

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA414914394

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 64af1bb4-86df-41c1-adc6-2b041e26e8d8

Approved on: 2025-03-10

Published on: 2025-03-28

HGVS expressions

NM_000132.3:c.1420G>T

NC_000023.11:g.154965993C>A

CM000685.2:g.154965993C>A

NC_000023.10:g.154194268C>A

CM000685.1:g.154194268C>A

NC_000023.9:g.153847462C>A

NG_011403.1:g.61731G>T

NG_011403.2:g.61731G>T

ENST00000360256.9:c.1420G>T

ENST00000647125.1:c.*1296G>T

ENST00000360256.8:c.1420G>T

ENST00000483822.2:n.240G>T

NM_000132.4:c.1420G>T

Likely Pathogenic

PM2_Supporting PP3 PM5 PP4_Moderate

PS4 PM1

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 variant, NM_000132.3(F8):c.1420G>T, predicts a missense change, Gly474Trp, which is not reported in gnomAD v2.1.1 or v3. This variant has been reported in at least one male patient with severe hemophilia A in the literature meeting PP4_Moderate criteria (PMID: 19473408). Another nucleotide change at the same codon, c.1421G>A; p.Gly474Glu is classified as pathogenic by CFD-VCEP meeting the PM5 criteria. The variant has a REVEL score of 0.952 (threshold >0.6) meeting PP3 criteria. In summary, 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 F8: PP4_Moderate, PP3, PM2_Supporting, PM5.

PM2_Supporting

Gly474Trp is absent from gnomAD v2.1.1 and v3.

PP3

REVEL score of 0.952 (threshold: >0.6) and CADD score of 28.1 (threshold: >21) meet criteria for PP3. SpliceAI acceptor/donor loss score of 0.01.

PM5

Another nucleotide change at the same codon, c.1421G>A (p.Gly474Glu) is classified as pathogenic by CFD-VCEP

PP4_Moderate

Proband with severe hemophilia A. Performed MLPA to access for del/dups.

PS4

Applying proband for PP4 code

PM1

Gly474Trp occurs in the A2 domain. PM1 is not applied at this time.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.