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.2138A>T

CA414904027

2691907 (ClinVar)

Gene: F8 (HGNC:2157)

Condition: hemophilia A (MONDO:0010602)

Inheritance Mode: X-linked inheritance

UUID: e39cdc6c-fa4c-483d-bc9e-04b440156fed

Approved on: 2025-03-10

Published on: 2025-03-28

HGVS expressions

NM_000132.4:c.2138A>T

NC_000023.11:g.154931652T>A

CM000685.2:g.154931652T>A

NC_000023.10:g.154159927T>A

CM000685.1:g.154159927T>A

NC_000023.9:g.153813121T>A

NG_011403.1:g.96072A>T

NG_011403.2:g.96072A>T

ENST00000360256.9:c.2138A>T

ENST00000647125.1:c.*1804A>T

ENST00000360256.8:c.2138A>T

NM_000132.3:c.2138A>T

Likely Pathogenic

PS3 PP3 PM2_Supporting PS4_Supporting PP1_Moderate

Evidence Links 1

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 c.2138A>T; p.Asn713Ile variant is completely absent from gnomAD v2.1.1 and v3.1.1. This missense variant has a REVEL score of 0.803 and meets PP3 criteria (threshold >0.6). One large Danish family with mild hemophilia A, with well over 3 meioses of variant segregation, is reported in the literature, meeting F8 phenotype criteria for PS4_Supporting and PP1_Moderate (PMID: 10886198). Monkey COS-1 cells with variant demonstrated decreased factor VIII antigen and activity levels discrepant between 1- and 2-stage assays, which meets PS3 criteria. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS3, PS4_Supporting, PP1_Moderate, PM2_Supporting, PP3.

PS3

Mutant expressed COS-1 monkey kidney cells showed decreased F8 antigen (~25%) and discrepant F8 activity (1 stage ~20%; 2 stage ~10%).

Full-length cDNAs containing variant generated by oligonucleotide site-directed mutagenesis were expressed in COS-1 monkey kidney cells showed decreased F8 antigen (~25%) and discrepant F8 activity (1 stage ~20%; 2 stage ~10%). PubMed:12428094

PP3

REVEL score is 0.803, which is above 0.6 cutoff.

PM2_Supporting

Variant is absent from gnomAD v2.1.1 and v3.

PS4_Supporting

Variant is absent in gnomAD v2.1.1 and v3.1 and present in a proband from a large Danish family.

PP1_Moderate

Variant segregates in large Danish family with more than 6 meioses, but capping at PP1_Moderate strength because segregations are from only 1 family.

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.