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.5822A>G (p.Asn1941Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA255184

10294 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: a2b52c30-02cc-49a6-9a79-849230686deb

Approved on: 2024-02-02

Published on: 2024-07-11

HGVS expressions

NM_000132.3:c.5822A>G

NM_000132.3(F8):c.5822A>G (p.Asn1941Ser)

NC_000023.11:g.154904082T>C

CM000685.2:g.154904082T>C

NC_000023.10:g.154132357T>C

CM000685.1:g.154132357T>C

NC_000023.9:g.153785551T>C

NG_011403.1:g.123642A>G

NG_011403.2:g.123642A>G

ENST00000360256.9:c.5822A>G

ENST00000360256.8:c.5822A>G

NM_000132.4:c.5822A>G

Pathogenic

PP4_Moderate PM2_Supporting PS4 PS3 PP1 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.5822A>G (p.Asn1941Ser) variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. This missense variant has a REVEL score of 0.943 (>0.6) and meets criteria for PP3. At least 80 probands have been reported in the literature and from internal laboratory data who meet the F8 phenotype criteria meeting thresholds for PS4_Very strong (>8 probands) and PP4_Moderate. Two brothers have been reported with severe hemophilia A, which meets the PP1 criteria (PMID: 15996930). Functional evidence from PMID: 21217077 shows that the variant results in a secretory defect based on barely detectable levels of antigen and activity when expressed in BHK cells, which meets PS3 criteria. 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, PS3, PM2_Supporting, PP1, PP3.

PP4_Moderate

Male with severe hemophilia A who had full F8 and F9 gene sequencing and deletion/duplication analysis through the MLOF study.

PM2_Supporting

The c.5822A>G (p.Asn1941Ser) variant is completely absent from gnomAD v2.1.1 and v3.1.1

PS4

At least 80 probands have been reported in the literature and from internal laboratory data who meet the F8 phenotype criteria. The threshold for PS4_VeryStrong is met (>8 probands)

PS3

Functional evidence from PMID: 21217077: The Asn1941Ser variant was expressed in BHK-M cells resulted in barely detectable levels of FVIII activity (measured by OSA) and FVIII antigen (measured by ELISA) levels. In addition, authors show that the variant results in stalling of FVIII folding in the ER, preventing or delaying its transport to the Golgi, and therefore limiting the secretion of the protein. The intracellularly retained FVIII is shown to be functionally normal or near normal. Patients with this variant are reported with inhibitors, which may be due to the inability to produce sufficient amounts of FVIII antigen to generate immunologic tolerance.

PP1

At least two siblings have been reported with the variant and severe hemophilia A.

PP3

This missense variant has a REVEL score of 0.943 (>0.6) and meets criteria for PP3

Curation History

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