Variant: NM_000132.4:c.2087C>T

CA414909018

2775445 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

UUID: f30a06e3-0a1c-419f-9520-c67684ffe703

Approved on: 2024-02-02

Published on: 2024-07-11

HGVS expressions

NM_000132.4:c.2087C>T
NC_000023.11:g.154947724G>A
CM000685.2:g.154947724G>A
NC_000023.10:g.154175999G>A
CM000685.1:g.154175999G>A
NC_000023.9:g.153829193G>A
NG_011403.1:g.80000C>T
NG_011403.2:g.80000C>T
ENST00000360256.9:c.2087C>T
ENST00000647125.1:c.*1779+6168C>T
ENST00000360256.8:c.2087C>T
NM_000132.3:c.2087C>T

Pathogenic

• Met criteria codes: PM2_Supporting PP3 PS4 PP4_Moderate

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

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The c.2087C>T (p.Thr696Ile) variant is absent from males in gnomAD v2.1.1 & gnomAD v3. 1 allele is reported in gnomAD v3.1.1 meeting PM2_Supporting criteria. The missense variant has a REVEL score of 0.927 (>0.6) meeting PP3 criteria. The variant has been reported in at least 18 probands with mild hemophilia A meeting phenotypic criteria for F8 at the very strong evidence weight (PMID: 24845853 and My Life Our Future data - 29296726). This variant has also been associated with discrepant factor VIII activity levels (PMID: 32232366). 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_VeryStrong, PP4_Moderate, PP3, PM2_Supporting.

Met criteria codes

• PM2_Supporting: The c.2087C>T (p.Thr696Ile) variant is absent from males in gnomAD v2.1.1 & gnomAD v3. 1 allele is reported in gnomAD v3.1.1. (MAF - 0.00009480 in Latino/admixed American population). PM2_Supporting is met.
• PP3: The c.2087C>T (p.Thr696Ile) missense variant has a REVEL score of 0.927 (>0.6).
• PS4: There are well over 8 individuals with mild hemophilia A reported in the literature and internal laboratory data meeting F8-phenotype criteria. PS4_Very strong is applied.
• PP4_Moderate: Male with mild hemophilia A with 7% factor VIII activity level who had full F8 and F9 gene sequencing and deletion/duplication analysis through the MLOF study.