Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000132.3(F8):c.6744G>T (p.Trp2248Cys)

CA255218

10327 (ClinVar)

Gene: F8
Condition: hemophilia A
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: c1d2fdde-4edc-4ef1-abe6-0b2c9a311eb6
Approved on: 2024-02-02
Published on: 2024-07-11

HGVS expressions

NM_000132.3:c.6744G>T
NM_000132.3(F8):c.6744G>T (p.Trp2248Cys)
NC_000023.11:g.154860588C>A
CM000685.2:g.154860588C>A
NC_000023.10:g.154088863C>A
CM000685.1:g.154088863C>A
NC_000023.9:g.153742057C>A
NG_011403.1:g.167136G>T
NG_011403.2:g.167136G>T
ENST00000360256.9:c.6744G>T
ENST00000644698.1:c.477G>T
ENST00000330287.10:c.339G>T
ENST00000360256.8:c.6744G>T
NM_019863.2:c.339G>T
NM_000132.4:c.6744G>T
NM_019863.3:c.339G>T
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Pathogenic

Met criteria codes 3
PS4 PP3 PM2_Supporting

Evidence Links 0

Expert Panel

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_000132.3(F8):c.6744G>T (p.Trp2248Cys) is reported in at least 19 patients with mild, moderate or severe hemophilia A in the literature reviewed (PMID: 17222201, 18691168, 15921397, 1301932, 17610560). There are several additional probands with the variant reported in the EAHAD database, recorded from the literature and unpublished sources. There are also individuals reported with a history of inhibitor development to factor VIII replacement therapy (EAHAD/CDC Champs Databases). The variant is absent from gnomAD v2.1.1 and v3 meeting PM2_Supporting. This missense variant has a REVEL score of 0.925 (>0.6), meeting criteria for PP3. 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, PP3, PM2_Supporting.
Met criteria codes
PS4
At least 19 individuals who meet F8 phenotype criteria with mild-severe hemophilia A are reported in the literature (PMID: 17222201, 18691168, 15921397, 1301932, 17610560), meeting PS4_Very Strong.
PP3
The c.6744G>T (p.Trp2248Cys) missense variant has a REVEL score of 0.925 (>0.6)
PM2_Supporting
The c.6744G>T (p.Trp2248Cys) variant is completely absent from population databases (gnomAD v2.1.1/gnomAD v3)
Curation History
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