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.3637del (p.Ile1213fs)

CA255146

10253 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 19e2feae-a2b9-46b5-aa09-71123369b1ca

Approved on: 2024-06-25

Published on: 2024-07-10

HGVS expressions

NM_000132.4:c.3637del

NM_000132.4:c.3637delA

NM_000132.4(F8):c.3637del (p.Ile1213fs)

NC_000023.11:g.154930161del

CM000685.2:g.154930161del

NC_000023.10:g.154158436del

CM000685.1:g.154158436del

NC_000023.9:g.153811630del

NG_011403.1:g.97571del

NG_011403.2:g.97571del

ENST00000360256.9:c.3637del

ENST00000647125.1:c.*3303del

ENST00000360256.8:c.3637del

NM_000132.3:c.3637del

Pathogenic

PVS1 PS2_Very Strong PS4 PM2_Supporting

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 F8 c.3637del (p.Ile1213Phefs*5) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 14 and expected to result in nonsense-mediated mRNA decay. This variant is completely absent from males in gnomAD v2.1.1 and gnomAD v3. This variant has been reported in >16 probands with moderate to severe hemophilia, meeting phenotypic criteria for F8 (PMID: 15921397; PMID: 20533009; PMID: 8307558; PMID: 16601827). This variant has been reported both with and without the development of inhibitors. This variant is reported as de novo in at least seven probands with maternity confirmed in the affected male (PMID: 29381227). 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: PVS1, PS2_Very Strong, PS4_Very Strong, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023)

PVS1

The 1-bp deletion occurs in exon 14 which results in a PTC 5 codons downstream, within exon 14/26. NMD is predicted.

PS2_Very Strong

There are at least at least 7 probands meeting phenotypic criteria for F8 (>4 points), with confirmed de novo (maternity confirmed in an affected male) occurrence PMID: 29381227.

PS4

At least 8 individuals with severe Hemophilia A across 10 publications reported (202 cases registered in the EAHAD database) who meet F8 phenotype criteria specified by the CFD VCEP for PS4.

PM2_Supporting

The variant is is absent from males in population databases (gnomAD v2.1.1/gnomAD v3).

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