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.6046C>T (p.Arg2016Trp)

CA255197

10304 (ClinVar)

Gene: F8
Condition: hemophilia A
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 3d921025-1d2e-41c3-9200-a2d11c4ad044
Approved on: 2024-02-02
Published on: 2024-07-11

HGVS expressions

NM_000132.3:c.6046C>T
NM_000132.3(F8):c.6046C>T (p.Arg2016Trp)
NC_000023.11:g.154902120G>A
CM000685.2:g.154902120G>A
NC_000023.10:g.154130395G>A
CM000685.1:g.154130395G>A
NC_000023.9:g.153783589G>A
NG_011403.1:g.125604C>T
NG_011403.2:g.125604C>T
ENST00000360256.9:c.6046C>T
ENST00000360256.8:c.6046C>T
NM_000132.4:c.6046C>T
More

Pathogenic

Met criteria codes 4
PS4 PP3 PP4_Moderate 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 c.6046C>T (p.Arg2016Trp) variant is completely absent from gnomAD v2.1.1 and gnomAD v3 meeting PM2_Supporting. This missense variant has a REVEL score of 0.822 (>0.6) meeting PP3 criteria. More than 46 probands are reported with the variant and moderate-severe hemophilia A in the literature and internal laboratory data (PMID: 29296726, 20102490, 18387975), meeting F8 phenotype criteria. This variant has been associated with discrepant factor VIII activity levels (PMID: 32232366). This variant has also been reported in individuals with a history of inhibitor development to factor replacement therapy (EAHAD database). 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: PS4_Very Strong, PP4_Moderate, PP3, PM2_Supporting.
Met criteria codes
PS4
More than 46 probands are reported with the variant and moderate-severe hemophilia A in the literature and internal laboratory data (PMID: 29296726, 20102490, 18387975), meeting F8 phenotype criteria. The threshold for PS4_Very Strong is met (>8).
PP3
This missense variant has a REVEL score of 0.822 (>0.6) and meets criteria for PP3.
PP4_Moderate
Male with severe hemophilia A who had full F8 and F9 gene sequencing and deletion/duplication analysis.
PM2_Supporting
The c.6046C>T (p.Arg2016Trp) variant is completely absent from gnomAD v2.1.1 and gnomAD v3.
Curation History
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