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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000132.4:c.1899G>T

CA414910251

2775444 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: bc8dc28d-54fd-4af4-95fd-9e395c0344e4

Approved on: 2024-02-02

Published on: 2024-07-11

HGVS expressions

NM_000132.4:c.1899G>T

NC_000023.11:g.154953896C>A

CM000685.2:g.154953896C>A

NC_000023.10:g.154182171C>A

CM000685.1:g.154182171C>A

NC_000023.9:g.153835365C>A

NG_011403.1:g.73828G>T

NG_011403.2:g.73828G>T

ENST00000360256.9:c.1899G>T

ENST00000647125.1:c.*1775G>T

ENST00000360256.8:c.1899G>T

NM_000132.3:c.1899G>T

Pathogenic

PP4_Moderate PS4 PP1 PP3 PM2_Supporting

PM5

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.1899G>T (p.Met633Ile) variant is completely absent from population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This missense variant has a REVEL score of 0.88 (>0.6) meeting PP3. At least 9 individuals with hemophilia A (mix of severities from severe to mild reported) from the literature are reported with the Met633Ile variant (PMID: 29296726, PMID: 19369668, PMID: 9886318 and PMID: 18691168) meeting PS4_Very strong and PP4_Moderate. 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 F8/F9: PS4_Very strong, PP4_Moderate, PP3, PM2_Supporting.

PP4_Moderate

Male with mild hemophilia A with 11% factor VIII activity level who had full gene sequencing for F8 and F9 with deletion/duplication analysis.

PS4

At least 8 individuals from the literature and internal laboratory data are reported with mild hemophilia A and the Met633Ile variant.

PP1

Two members of a family were genotyped. The degree of relationship was unknown, so the code is applied at the supporting level.

PP3

The c.1899G>T (p.Met633Ile) missense variant has a REVEL score of 0.88 (>0.6)

PM2_Supporting

This missense variant is completely absent from population databases (gnomAD v2.1.1/gnomAD v3)

PM5

2 variants at the same residue, Met633Val and Met633Thr, are reported in the EAHAD database. PM5 is not considered as the two variants have not yet been evaluated by the CFD-VCEP.

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.