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.6429+2T>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA414899265

2775450 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 46c40028-f5d9-4236-8b9c-3b05d2c95293

Approved on: 2024-02-09

Published on: 2024-07-11

HGVS expressions

NM_000132.4:c.6429+2T>A

NC_000023.11:g.154896075A>T

CM000685.2:g.154896075A>T

NC_000023.10:g.154124350A>T

CM000685.1:g.154124350A>T

NC_000023.9:g.153777544A>T

NG_011403.1:g.131649T>A

NG_011403.2:g.131649T>A

ENST00000360256.9:c.6429+2T>A

ENST00000360256.8:c.6429+2T>A

NM_000132.3:c.6429+2T>A

Pathogenic

PM2_Supporting PVS1_Strong PS4

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 c.6429+2T>A variant causes in frame skipping of exon 22 resulting in a protein lacking 52 aa of the C2 domain (PMID: 15670040), which meets PVSS1_Strong criteria. This variant has been identified in at least 4 individuals with severe hemophilia A (PMID: 15670040, 19740093, 12195713) and is completely absent from gnomAD v2.1.1 and v3.1.1, which meets criteria for PS4_Strong and PM2_Supporting. 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: PVS1_Strong, PS4, PM2_Supporting.

PM2_Supporting

Variant is absent in gnomAD v2.1.1 and v3.1.

PVS1_Strong

Variant causes in frame skipping of exon 22 resulting in a protein lacking 52 aa of the C2 domain.

PS4

Four probands noted to have severe hemophilia A found in literature, and variant is absent in gnomAD v2.1.1 and v3.1.

Curation History

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