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_000132.4(F8):c.7021G>A (p.Glu2341Lys)

CA414896766

993916 (ClinVar)

Gene: F8 (HGNC:2157)

Condition: hemophilia A (MONDO:0010602)

Inheritance Mode: X-linked inheritance

UUID: 2688b738-ba27-4952-af05-269db4e4de11

Approved on: 2025-05-02

Published on: 2025-05-02

HGVS expressions

NM_000132.4(F8):c.7021G>A (p.Glu2341Lys)

NM_000132.4:c.7021G>A

NC_000023.11:g.154837632C>T

CM000685.2:g.154837632C>T

NC_000023.10:g.154065907C>T

CM000685.1:g.154065907C>T

NC_000023.9:g.153719101C>T

NG_011403.1:g.190092G>A

NG_033065.1:g.2031G>A

NG_011403.2:g.190092G>A

ENST00000360256.9:c.7021G>A

ENST00000644698.1:c.754G>A

ENST00000330287.10:c.616G>A

ENST00000360256.8:c.7021G>A

NM_000132.3:c.7021G>A

NM_019863.2:c.616G>A

NM_019863.3:c.616G>A

Likely Pathogenic

PM2_Supporting PP4_Moderate PS4 PP3

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.7021G>A (p.Glu2341Lys) missense variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This missense variant has a REVEL score of 0.864 (>0.6) meeting PP3. This variant has been reported in at least five probands in the literature (PMID: 31829478, 21070499, 18691168, 33706050, 16879218) meeting phenotypic criteria for F8 (PP4_Moderate & PS4). In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4, PP4_Moderate, PP3, PM2_Supporting.

PM2_Supporting

The c.7021G>A (p.Glu2341Lys) missense variant is completely absent from gnomAD v2.1.1 and v3.1.2

PP4_Moderate

1 West African proband (from Côte d'Ivoire) reported with moderate hemophilia A and the Glu2341Lys variant. Variant was identified using NGS platform to detect SNV and CNV.

PS4

At least six probands with hemophilia A are reported with the Glu2341Lys variant with varying severities. One proband was excluded for caution due to not being peer reviewed publication. One moderate proband is being used for PP4 (PS4 total 4 points).

PP3

This missense variant has a REVEL score of 0.864 and meets PP3 criteria (threshold >0.6)

Curation History

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