Table of 36 Missense Mutations Studied, With FVIII:C and FVIII:Ag Levels, Clinical Severity, Level of Conservation and Comments on Possible Molecular Pathology
| Mutation . | ID* . | FVIII:C (%) . | FVIII:Ag (%) . | Clinical Severity . | Conservation† . | Hypothetical Pathology . |
|---|---|---|---|---|---|---|
| Y114C | HP19 | 6.3 | 10.7 | Mild | YYYYYY | Free Cys hinders correct folding |
| T1181 | HP20 | 2.0 | 10.7 | Moderate | TTTTTT | Steric clash with D116 in core |
| V162M | HP25 | 5.3 | 14 | Mild | VVEVVI | No assignable reason for phenotype |
| K166T | JH139 | 8.0 | 9.8 | Mild | KKEEKK | Loss of positive charge |
| S170L | LKC | 3.5 | 8.7 | Mild | SSSSSS | Strain in core, possible loss of H-bond with K166 main chain carbonyl |
| D203V | HP28 | 2.0 | 8.5 | Mild | DDDDDD | Loss of negative charge |
| E272G | JH20 | 2.0 | 3.5 | Moderate | EENNHH | Possible loss of H-bond with L307 main chain carbonyl |
| T275I | HP29 | 4.8 | 20.2 | Moderate | TTVVAA | Possible loss H-bond with H274 main chain carbonyl |
| R282H | JH86 | <1 | 18 | Severe | RRKKHR | Modification of A1/A2 interaction via D525 |
| S289L | JH152 | 37 | 106 | Mild | SSVVFF | Modification of A1/A3 interaction via Y1979 |
| T295A | HP32 | 9.5 | 11.6 | Mild | TTTTDD | No assignable reason for phenotype |
| C329S | Lisboa2 | 2.6 | 3.2 | Moderate | CCCCCC | Loss of conserved disulphide link |
| L412F | JH131 | 7.0 | 6.4 | Mild | LLLLFF | Steric clash with S409 in core |
| K425R | JH74 | <1 | 5.0 | Severe | KKKKKK | Steric strain in core |
| A469G | HP38 | 2.3 | 45.3 | Moderate | AAAAGG | No assignable reason for phenotype |
| I475T | HP39 | 5.5 | 8.8 | Mild | IIIIII | No assignable reason for phenotype |
| G479R | Porto1 | 17.8 | 31.6 | Mild | GGGGGG | Steric clash with R531 in core |
| D525N | MS | 6.0 | 61 | Moderate | DDDDDD | Modification of A1/A2 interaction |
| R527W | DG | 15.0 | 126 | Mild | RRQQVV | Disturbance of FIXa binding-site |
| R531H | HP46 | 23.5 | 33.2 | Mild | RRRRKK | Modification of A1/A2 interaction via R282 |
| D542G | JH63 | <1 | 5.0 | Severe | DDDDDD | Loss of negative charge |
| S558F | JH151 | 21 | 175 | Mild | SSSSSS | Steric clash with C554/Y555 round FIXa binding-site |
| I566T | FW | 4 | 200 | Moderate | IMRRKK | Predicted new N-glycosylation at N564 close to FIXa binding-site |
| V634A | JH156 | 5 | 138 | Mild | VVTTSS | No assignable reason for phenotype |
| A644V | JH136 | 14 | 25 | Mild | AATTNN | Modification of A1/A2 interaction |
| F658L | HP49 | 5.1 | 50.5 | Mild | FFFFYY | Decrease in core volume |
| A704T | HP51 | 4.5 | 5.5 | Moderate | AALLQQ | No assignable reason for phenotype |
| G1750R | HP77 | 22 | 23.5 | Mild | GGGGRK | Addition of positive charge and bulky sidechain |
| L1756V | HP83 | 5.0 | 1.5 | Mild | LLLLLL | No assignable reason for phenotype |
| M1772T | JH116 | <1 | 72 | Severe | MMQQKK | Predicted new N-glycosylation at N1770 close to FIXa binding-site |
| R1781H | HP84 | 2.0 | 4.7 | Moderate | RRRRRR | No assignable reason for phenotype |
| P1825S | HP88 | 12 | 18.1 | Mild | PPPPAA | Close to FIXa binding-site |
| H1848R | HP89 | 1.5 | 20.1 | Moderate | HHHHIY | Modification of A2/A3 interaction via D696 |
| R1941Q | JH33 | 4.5 | 20 | Mild | RRRRNN | Close to FIXa binding-site |
| G1948D | Porto2 | 7.4 | 48.7 | Mild | GGGGGG | Close to A2/A3 interface |
| H1961Y | HP91 | 10.5 | 7.8 | Mild | HHQQHH | Increases core energy |
| Mutation . | ID* . | FVIII:C (%) . | FVIII:Ag (%) . | Clinical Severity . | Conservation† . | Hypothetical Pathology . |
|---|---|---|---|---|---|---|
| Y114C | HP19 | 6.3 | 10.7 | Mild | YYYYYY | Free Cys hinders correct folding |
| T1181 | HP20 | 2.0 | 10.7 | Moderate | TTTTTT | Steric clash with D116 in core |
| V162M | HP25 | 5.3 | 14 | Mild | VVEVVI | No assignable reason for phenotype |
| K166T | JH139 | 8.0 | 9.8 | Mild | KKEEKK | Loss of positive charge |
| S170L | LKC | 3.5 | 8.7 | Mild | SSSSSS | Strain in core, possible loss of H-bond with K166 main chain carbonyl |
| D203V | HP28 | 2.0 | 8.5 | Mild | DDDDDD | Loss of negative charge |
| E272G | JH20 | 2.0 | 3.5 | Moderate | EENNHH | Possible loss of H-bond with L307 main chain carbonyl |
| T275I | HP29 | 4.8 | 20.2 | Moderate | TTVVAA | Possible loss H-bond with H274 main chain carbonyl |
| R282H | JH86 | <1 | 18 | Severe | RRKKHR | Modification of A1/A2 interaction via D525 |
| S289L | JH152 | 37 | 106 | Mild | SSVVFF | Modification of A1/A3 interaction via Y1979 |
| T295A | HP32 | 9.5 | 11.6 | Mild | TTTTDD | No assignable reason for phenotype |
| C329S | Lisboa2 | 2.6 | 3.2 | Moderate | CCCCCC | Loss of conserved disulphide link |
| L412F | JH131 | 7.0 | 6.4 | Mild | LLLLFF | Steric clash with S409 in core |
| K425R | JH74 | <1 | 5.0 | Severe | KKKKKK | Steric strain in core |
| A469G | HP38 | 2.3 | 45.3 | Moderate | AAAAGG | No assignable reason for phenotype |
| I475T | HP39 | 5.5 | 8.8 | Mild | IIIIII | No assignable reason for phenotype |
| G479R | Porto1 | 17.8 | 31.6 | Mild | GGGGGG | Steric clash with R531 in core |
| D525N | MS | 6.0 | 61 | Moderate | DDDDDD | Modification of A1/A2 interaction |
| R527W | DG | 15.0 | 126 | Mild | RRQQVV | Disturbance of FIXa binding-site |
| R531H | HP46 | 23.5 | 33.2 | Mild | RRRRKK | Modification of A1/A2 interaction via R282 |
| D542G | JH63 | <1 | 5.0 | Severe | DDDDDD | Loss of negative charge |
| S558F | JH151 | 21 | 175 | Mild | SSSSSS | Steric clash with C554/Y555 round FIXa binding-site |
| I566T | FW | 4 | 200 | Moderate | IMRRKK | Predicted new N-glycosylation at N564 close to FIXa binding-site |
| V634A | JH156 | 5 | 138 | Mild | VVTTSS | No assignable reason for phenotype |
| A644V | JH136 | 14 | 25 | Mild | AATTNN | Modification of A1/A2 interaction |
| F658L | HP49 | 5.1 | 50.5 | Mild | FFFFYY | Decrease in core volume |
| A704T | HP51 | 4.5 | 5.5 | Moderate | AALLQQ | No assignable reason for phenotype |
| G1750R | HP77 | 22 | 23.5 | Mild | GGGGRK | Addition of positive charge and bulky sidechain |
| L1756V | HP83 | 5.0 | 1.5 | Mild | LLLLLL | No assignable reason for phenotype |
| M1772T | JH116 | <1 | 72 | Severe | MMQQKK | Predicted new N-glycosylation at N1770 close to FIXa binding-site |
| R1781H | HP84 | 2.0 | 4.7 | Moderate | RRRRRR | No assignable reason for phenotype |
| P1825S | HP88 | 12 | 18.1 | Mild | PPPPAA | Close to FIXa binding-site |
| H1848R | HP89 | 1.5 | 20.1 | Moderate | HHHHIY | Modification of A2/A3 interaction via D696 |
| R1941Q | JH33 | 4.5 | 20 | Mild | RRRRNN | Close to FIXa binding-site |
| G1948D | Porto2 | 7.4 | 48.7 | Mild | GGGGGG | Close to A2/A3 interface |
| H1961Y | HP91 | 10.5 | 7.8 | Mild | HHQQHH | Increases core energy |
Unique patient identifier: where multiple reports occur in the hemophilia A database, only the first entry with full phenotype is given here.
This column gives the single letter amino-acid code for the wild-type residues in this position in (L-R): human FVIII, murine FVIII, human FV, bovine FV, rat Cp, and human Cp.