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_000132.4(F8):c.6976C>T (p.Arg2326Ter)

CA255007

10085 (ClinVar)

Gene: F8
Condition: hemophilia A
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 4e8e0239-4155-44c7-b22f-2aea4ebb9066
Approved on: 2024-06-19
Published on: 2024-07-11

HGVS expressions

NM_000132.4:c.6976C>T
NM_000132.4(F8):c.6976C>T (p.Arg2326Ter)
NC_000023.11:g.154837677G>A
CM000685.2:g.154837677G>A
NC_000023.10:g.154065952G>A
CM000685.1:g.154065952G>A
NC_000023.9:g.153719146G>A
NG_011403.1:g.190047C>T
NG_033065.1:g.1986C>T
NG_011403.2:g.190047C>T
ENST00000360256.9:c.6976C>T
ENST00000644698.1:c.709C>T
ENST00000330287.10:c.571C>T
ENST00000360256.8:c.6976C>T
NM_000132.3:c.6976C>T
NM_019863.2:c.571C>T
NM_019863.3:c.571C>T
More

Pathogenic

Met criteria codes 6
PP4_Moderate PS4 PP1 PVS1_Moderate PS2_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.6976C>T (p.Arg2326Ter) creates a premature stop codon in exon 26, which is the last exon of the F8 gene. Therefore, protein is not expected to undergo NMD and meets PVS1_Strong. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. More than 20 patients are reported in the literature with severe/moderate hemophilia A, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate. The variant was also reported in two affected brothers and their carrier mother, which meets criteria for PP1 (PMID: 2987704). There is also at least one report of a de novo case where maternity was not confirmed, meeting PS2_Moderate (PMID: 2104741). 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 F9: PVS1_Strong, PS4_Very strong, PS2_Moderate, PP4_Moderate, PM2_Supporting, PP1.
Met criteria codes
PP4_Moderate
Counting one MLOF proband
PS4
Variant has been report in more than 20 individuals in the literature with severe/moderate hemophilia A. Therefore, criteria for PS4_Very strong is met.
PP1
Variant identified in two affected brothers and their mother (2 meioses).
PVS1_Moderate
Variant causes an in frame stop that is not expected to undergo NMD.
PS2_Moderate
1 severe hemophilia A patient with de novo variant; maternity not confirmed.
PM2_Supporting
Variant is absent in males in gnomAD v.2.1.1 and v3.1.
Curation History
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