Variant: NM_000132.4(F8):c.1468A>G (p.Arg490Gly)

CA414912841

804141 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

UUID: d9e7cff7-fcf3-4c36-8cbb-411d62077c9d

Approved on: 2025-04-04

Published on: 2025-04-04

HGVS expressions

NM_000132.4:c.1468A>G
NM_000132.4(F8):c.1468A>G (p.Arg490Gly)
NC_000023.11:g.154961144T>C
CM000685.2:g.154961144T>C
NC_000023.10:g.154189419T>C
CM000685.1:g.154189419T>C
NC_000023.9:g.153842613T>C
NG_011403.1:g.66580A>G
NG_011403.2:g.66580A>G
ENST00000360256.9:c.1468A>G
ENST00000647125.1:c.*1344A>G
ENST00000360256.8:c.1468A>G
NM_000132.3:c.1468A>G

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PS4_Moderate PP1 PP3

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.1468A>G variant in F8 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 490 (p.Arg490Gly). There a My Life Our Future proband with mild hemophilia A associated with this variant, meeting phenotypic criteria for F8 (PP4_Moderate, PMID: 29296726, PMID: 35770352). This proband has at least 2 affected male relatives with mild hemophilia A meeting PP1 (PMID: 29296726). This variant has been reported in 3 additional probands meeting phenotypic criteria for hemophilia A meeting PS4_Moderate (PMIDs: 10404764, 18691168, & internal laboratory data). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1.0 meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.887, which is above the threshold of >=0.6, evidence that correlates with impact to F8 function meeting PP3. In summary, this variant meets the criteria to be classified as likely pathogenic for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): PP4_Moderate, PP1, PS4_Moderate PM2_Supporting, PP3.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Also absent from gnomAD v4.1.0.
• PP4_Moderate: There is at least 1 proband with mild Hemophilia A, meeting phenotypic criteria for F8. (PP4_moderate, PMID: 29296726)
• PS4_Moderate: This variant has been reported in 3 probands meeting phenotypic criteria for hemophilia A (PMID: 10404764, PMID: 18691168, internal laboratory data) meeting PS4_moderate.
• PP1: 3 related males with mild hemophilia A from PMID: 29296726 from internal communication.
• PP3: The computational predictor REVEL gives a score of 0.887, which is above the threshold of >=0.6, evidence that correlates with impact to F8 function (PP3).