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_000132.3(F8):c.1063C>T (p.Arg355Ter)

CA255031

10139 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: ecf66ee1-bbaa-44e7-ba8d-3ac575927b66

Approved on: 2024-02-02

Published on: 2024-07-11

HGVS expressions

NM_000132.3:c.1063C>T

NM_000132.3(F8):c.1063C>T (p.Arg355Ter)

NC_000023.11:g.154966634G>A

CM000685.2:g.154966634G>A

NC_000023.10:g.154194909G>A

CM000685.1:g.154194909G>A

NC_000023.9:g.153848103G>A

NG_011403.1:g.61090C>T

NG_011403.2:g.61090C>T

ENST00000360256.9:c.1063C>T

ENST00000647125.1:c.*939C>T

ENST00000360256.8:c.1063C>T

NM_000132.4:c.1063C>T

Pathogenic

PS2_Moderate PM2_Supporting PVS1 PS4 PP1 PP4_Moderate

PS3

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.1063C>T (p.Arg355Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 8/26 and expected to result in nonsense-mediated mRNA decay, which meets PVS1 criteria. At least 20 probands from the literature reviewed below are reported to be hemizygous for the Arg355Ter variant, with severe Hemophilia A (FVIII:C <1%), which meets the PP4_Moderate and PS4_Very strong criteria. Inhibitors are reported in a few of these patients. One de novo occurrence without confirmation of maternity or paternity and an expected severe phenotype is reported in PMID: 29381227, which meets the PS2_Moderate criteria. Two siblings in one family in PMID: 15996930 are noted to have severe HA and the Arg355Ter variant, which meets PP1 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/F9: PVS1, PS4_Very Strong, PP4_Moderate, PS2_Moderate, PP1, PM2_Supporting.

PS2_Moderate

1 de novo occurrence without confirmation of maternity or paternity and an expected severe phenotype is reported in PMID: 29381227 (1 point for de novo evidence = moderate).

PM2_Supporting

The c.1063C>T (p.Arg355Ter) variant is absent from males in population databases; but it is reported at a frequency of 0.00001224 (1/81723 non-Finnish European alleles) in gnomAD v2.1.1.

PVS1

The c.1063C>T (p.Arg355Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 8/26 and expected to result in nonsense-mediated mRNA decay.

PS4

At least 20 probands from the literature reviewed below are reported to be hemizygous for the Arg355Ter variant, with severe Hemophilia A (FVIII:C <1%). Inhibitors are reported in a few of these patients. Probands meet F8 phenotype criteria to apply PS4_Very Strong.

PP1

Two siblings in one family in PMID: 15996930 are noted to have severe HA and the Arg355Ter variant.

PP4_Moderate

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

PS3

PMID: 26915717 describes characterization of FVIII B domain variants by evaluating FVIII:C and FVIII:Ag levels in the conditioned medium following transient transfection in COS-1 cells. Arg355Ter was used as a pathogenic control. It is noted that neither FVIII:C nor FVIII:Ag were detectable for this nonsense variant. The evidence is noted for information; however, PS3 is not applied when NMD is predicted and PVS1 is met.

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