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_000133.3(F9):c.835G>A (p.Ala279Thr)

CA277507

216926 (ClinVar)

Gene: F9
Condition: hemophilia B
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 4982024e-218e-4597-8dff-d780dd246d0a
Approved on: 2024-02-09
Published on: 2024-07-11

HGVS expressions

NM_000133.3:c.835G>A
NM_000133.3(F9):c.835G>A (p.Ala279Thr)
NC_000023.11:g.139560852G>A
CM000685.2:g.139560852G>A
NC_000023.10:g.138643011G>A
CM000685.1:g.138643011G>A
NC_000023.9:g.138470677G>A
NG_007994.1:g.35117G>A
ENST00000218099.7:c.835G>A
ENST00000643157.1:n.1502G>A
ENST00000218099.6:c.835G>A
ENST00000394090.2:c.721G>A
NM_001313913.1:c.721G>A
NM_000133.4:c.835G>A
NM_001313913.2:c.721G>A
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Pathogenic

Met criteria codes 5
PP4_Moderate PM2_Supporting PS4 PM1 PP3
Not Met criteria codes 1
PP1

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 F9 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Coagulation Factor Deficiency VCEP
The NM_000133.3:c.835G>A variant that results in the Ala279Thr missense change is absent from gnomAD v2.1.1 and v3, meeting PM2_Supporting. It is located within the peptidase S2 domain, which is deemed critical to protein function, meeting PM1. More than 59 male patients with mild hemophilia B are reported hemizygous for this variant in the literature, meeting PS4_Very strong and PP4_Moderate criteria (PMID: 29296726, 29656491). It is noted as a founder variant but may also have arisen de novo as a recurrent variant and is found in multiple ethnicities. The variant has a REVEL score of 0.765 (>0.6) and CADD score of 23 (>21) which meet the thresholds recommended for PP3. In summary, the 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: PS4_Very Strong, PM1, PP3, PP4_Moderate, PM2_Supporting.
Met criteria codes
PP4_Moderate
Male with mild hemophilia B with 6% factor IX activity level who had F8 and F9 full gene sequencing and deletion/duplication analysis.
PM2_Supporting
The variant is absent from gnomAD v2.1.1 and v3.
PS4
At least 59 patients with the Ala279Thr variant are reported across 27 publications from different ethnicities, meeting criteria for PS4_Very Strong. This is a conservative estimate, it is likely that the variant is present at a higher frequency among HB patients. 94 HB patients are recorded in the EAHAD database. The variant is mostly associated with mild disease, with a mean FIX:C of 11.21 U/dl (PMID: 19699296). Inhibitors are NOT reported in patients.
PM1
The variant at position 279 occurs within the peptidase S1 domain, which is determined by the CFD VCEP to be critical to the function of the F9 protein
PP3
REVEL score of 0.765 (>0.6) and CADD score of 23 (>21) meet the thresholds recommended for PP3 by the CFD VCEP
Not Met criteria codes
PP1
From internal laboratory data: Patient with mild HB (FIX:C = 19%) is reported to have two brothers with HB; however, their genotyping information is unavailable.
Curation History
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