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]

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

CA414896766

993916 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

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

Approved on: 2024-07-08

Published on: 2024-07-10

HGVS expressions

NM_000132.4:c.7021G>A

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

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

Uncertain Significance

PP3 PM2_Supporting PS4_Moderate

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). This variant has been reported in at least three probands in the literature (PMID: 31829478, 21070499, 18691168) associated with severe hemophilia A (1-3 probands & 0 gnomAD alleles) meeting phenotypic criteria for F8. This missense variant has a REVEL score of 0.864 (>0.6). In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_moderate, PP3, PM2_Supporting.

PP3

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

PM2_Supporting

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

PS4_Moderate

At least three probands are reported in the literature with the Glu2341Lys variant and severe hemophilia A, meeting criteria for PS4_Moderate.

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