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.1214T>G (p.Ile405Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA255098

10208 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 09c5f952-1d82-42e6-b221-8818af0dd1db

Approved on: 2024-06-19

Published on: 2024-07-11

HGVS expressions

NM_000132.3:c.1214T>G

NM_000132.3(F8):c.1214T>G (p.Ile405Ser)

NC_000023.11:g.154966483A>C

CM000685.2:g.154966483A>C

NC_000023.10:g.154194758A>C

CM000685.1:g.154194758A>C

NC_000023.9:g.153847952A>C

NG_011403.1:g.61241T>G

NG_011403.2:g.61241T>G

ENST00000360256.9:c.1214T>G

ENST00000647125.1:c.*1090T>G

ENST00000360256.8:c.1214T>G

ENST00000483822.2:n.34T>G

NM_000132.4:c.1214T>G

Likely Pathogenic

PP4_Moderate PP3 PS4_Moderate PM2_Supporting PM5_Supporting

PM1

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 variant, NM_000132.3(F8):c.1214T>G causes a missense change, Ile405Ser, which is not reported in gnomAD v2.1.1 or v3 or v4. This variant has been reported in at least three patients with Hemophilia A in the literature (PS4_Moderate, PP4_Moderate, PMIDs: 8307558). The variant has a REVEL score of 0.985 (PP3 threshold >0.6). Another variant at the same codon, Ile405Thr, is curated by the Coagulation Factor Deficiency Variant Curation Expert Panel as likely pathogenic (PM5_Supporting). In summary, 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: PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting.

PP4_Moderate

One patient with this variant displayed FVIII:C <1%, and deletion/duplication analysis was performed, which is highly specific for Hemophilia A (PP4, PMID: 29296726).

PP3

REVEL score of 0.985 (threshold >0.6) and CADD score of 26.3 (threshold >21) meet criteria for PP3.

PS4_Moderate

This variant has been reported in 2 probands meeting F8 phenotype criteria (PS4_Moderate; PMID: 8307558 and CHAMP US database).

PM2_Supporting

Ile405Ser is absent from gnomAD v2 and v3.

PM5_Supporting

c.1214T>C (p.Ile405Thr) is a variant at the same codon and is curated by the Coagulation Factor Deficiency VCEP to be likely pathogenic, meeting criteria for PM5_Supporting.

PM1

Ile405Ser occurs in the A2 domain. PM1 is not applied at this time.

Curation History

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