Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000132.3(F8):c.1660A>G (p.Ser554Gly)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA255116

10226 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: abad070d-72d1-4e21-af79-75e18849b027

Approved on: 2024-02-02

Published on: 2024-07-11

HGVS expressions

NM_000132.3:c.1660A>G

NM_000132.3(F8):c.1660A>G (p.Ser554Gly)

NC_000023.11:g.154957049T>C

CM000685.2:g.154957049T>C

NC_000023.10:g.154185324T>C

CM000685.1:g.154185324T>C

NC_000023.9:g.153838518T>C

NG_011403.1:g.70675A>G

NG_011403.2:g.70675A>G

ENST00000360256.9:c.1660A>G

ENST00000647125.1:c.*1536A>G

ENST00000360256.8:c.1660A>G

NM_000132.4:c.1660A>G

Pathogenic

PP4_Moderate PS4 PP3 PP1_Strong

PM2

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The c.1660A>G (p.Ser554Gly) missense variant has a REVEL score of 0.938 which meets PP3 criteria (threshold >0.6). This variant is present in 1 hemizygote in gnomAD v2.1.1 and therefore, does not meet criteria for rarity in the population. Fifty-three patients are reported in Johnsen, et. al. 2107 with mild/moderate hemophilia A and the Gly554Ser variant, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate (PMID: 29296726). The variant has been found to segregate with hemophilia A across 6 meioses among 4 different families, the PP1 criteria at the strong weight (Internal VCEP contributor). This variant has been reported in individuals who developed an inhibitor to factor replacement therapy and discrepant chromogenic and one-stage factor VIII activity levels (CDC CHAMPS database/Internal VCEP contributor). 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, PP1_Strong, PP4_Moderate, PP3.

PP4_Moderate

Counting 1 of numerous male probands with mild hemophilia A with full sequencing of the F8 and F9 genes with deletion and duplication analysis.

PS4

>8 individuals with mild/moderate hemophilia A reported in Johnsen, et al 2019 publication.

PP3

The REVEL score is 0.938 (cutoff greater than or equal to 0.6).

PP1_Strong

Variant has been seen in 6 meioses across 4 families (VCEP member clinical cohort).

PM2

Variant is present in one hemizygote in gnomAD v2.1.1.

Curation History

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