Table 1.
Functional analysis of new (noncharacterized) FH variants
| Transcript | Protein | Expression | GP hemolysis HR50 (0.71-1.29)* |
C3b binding BD50 (0.33-1.67)* |
DAA (<12.5)* |
FI cofactor activity (<2.5)* |
Functional- and expression-based classification |
|---|---|---|---|---|---|---|---|
| c.5G>C | R2T | N | 1.07 | 1.17 | 7.3 | 1.2 | Benign |
| c.32T>C | M11T | N | 1.19 | 1.32 | 7.2 | 1.4 | Benign |
| c.220C>T | L74F | N | 1.08 | 1.39 | 9.6 | 1.9 | Benign |
| c.242A>C | Q81P | N | 4.64 | 2.21 | 51.4 | 21.5 | Pathogenic |
| c.245A>G | K82R | N | 1.11 | 0.87 | 9.4 | 1.7 | Benign |
| c.272C>G | T91S | N | 1.03 | 1.74 | 8.8 | 1.6 | Benign |
| c.332T>A | V111E | N | 1.29 | 1.65 | 8.8 | 1.5 | Benign |
| c.400T>C | W134R | W | >8 | 2.40 | 73.1 | 87.3 | Pathogenic |
| c.451G>A | A151T | N | 1.26 | 0.82 | 9 | 2.2 | Benign |
| c.472G>A | V158I | N | 0.96 | 1.67 | 7.1 | 1.4 | Benign |
| c.476G>A | S159N | N | 1.18 | 1.12 | 10.6 | 1.8 | Benign |
| c.481G>T | A161S | N | 0.98 | 1.03 | 10.8 | 2.1 | Benign |
| c.484A>G | M162V | N | 0.79 | 0.69 | 7.3 | 1.7 | Benign |
| c.497G>T | R166L | N | 1.03 | 0.68 | 11.4 | 6.1 | Pathogenic |
| c.560A>T | D187V | N | 0.94 | 1.36 | 10.8 | 2.1 | Benign |
| c.592T>C | W198R | N | 3.66 | 3.16 | 33.3 | 56.9 | Pathogenic |
| c.595A>G | S199G | N | 1.81 | 3.17 | 17.8 | 7.1 | Pathogenic |
| c.647T>C | I216T | N | 1.18 | 1.35 | 7.9 | 1.7 | Benign |
| c.661A>G | I221V | N | 0.66 | 0.78 | 2.2 | 1.3 | Benign |
| c.773C>T | P258L | N | 1.72 | 2.71 | 17.8 | 4 | Pathogenic |
| c.908G>A | R303Q | N | 1.04 | 0.84 | 3.6 | 1.3 | Benign |
| c.974G>A | C325Y | W | 1.27 | — | 29 | 4.6 | Pathogenic |
| c.1022G>A | R341H | N | 0.86 | 1.27 | 9.5 | 1.8 | Benign |
| c.1064A>C | Y355S | W | 0.77 | — | 30.7 | 4.9 | Pathogenic |
| c.1507C>G | P503A | N | 0.94 | 0.83 | 2.3 | 1.2 | Benign |
| c.1548T>A | N516K | N | 1.15 | 1.72 | 9.8 | 2.2 | Benign |
| c.1565A>G | D522G | N | 0.96 | 1.41 | 6.7 | 2 | Benign |
| c.1591A>G | T531A | N | 1.22 | 1.25 | 9.1 | 2.1 | Benign |
| c.1652T>C | I551T | N | 1.26 | 1.29 | 8.7 | 1.5 | Benign |
| c.1745G>A | R582H | N | 0.80 | 1.17 | 11 | 2.3 | Benign |
| c.1825G>A | V609I | N | 0.86 | 1.03 | 7.1 | 1.8 | Benign |
| c.1922T>C | V641A | N | 1.09 | 1.22 | 10.1 | 1.5 | Benign |
| c.1949G>T | G650V | N | 1.14 | 0.94 | 9.8 | 2.5 | Benign |
| c.2056G>A | V686M | N | 1.01 | 1.20 | 8.4 | 1.9 | Benign |
| c.2120C>T | P707L | N | 1.01 | 1.78 | 8 | 1.9 | Benign |
| c.2461C>T | H821Y | N | 1.02 | 0.96 | 5.6 | 1.4 | Benign |
| c.2503G>T | V835L | N | 0.70 | 1.31 | 8.9 | 2 | Benign |
| c.2650T>C | S884P | N | 0.52 | 0.88 | 7.2 | 1.2 | Benign |
| c.2851T>C | Y951H | N | 0.89 | 1.33 | 11.5 | 2.1 | Benign |
| c.2879T>C | F960S | N | 1.05 | 0.95 | 2.5 | 1.2 | Benign |
| c.3050C>T | T1017I | N | 0.79 | 0.95 | 9.1 | 1.5 | Benign |
| c.3062A>T | Y1021F | N | 1.05 | 1.64 | 8.1 | 1.8 | Benign |
| c.3079G>C | A1027P | N | 0.87 | 0.89 | 3.1 | 1.3 | Benign |
| c.3160G>A | V1054I | N | 1.14 | 0.97 | 9.9 | 1.3 | Benign |
| c.3172T>C | Y1058H | N | 0.91 | 1.64 | 5.4 | 1.4 | Benign |
| c.3176T>C | I1059T | N | 1.00 | 0.87 | 6.1 | 1.6 | Benign |
| c.3178G>C | V1060L | N | 1.04 | 0.65 | 5.9 | 1.6 | Benign |
| c.3179T>C | V1060A | N | 1.03 | 1.32 | 7.4 | 1.4 | Benign |
| c.3181T>C | S1061P | N | 0.90 | 0.76 | 8.8 | 1.9 | Benign |
| c.3226C>G | Q1076E | N | 1.05 | 1.21 | 7.8 | 1.8 | Benign |
| c.3234G>T | R1078S | N | 0.95 | 1.01 | 3.9 | 1.3 | Benign |
| c.3264A>C | E1088D | N | 1.09 | 1.13 | 11.1 | 1.4 | Benign |
| c.3357C>G | D1119E | N | 2.34 | 2.18 | 21.9 | 9.5 | Pathogenic |
| c.3389C>T | P1130L | N | 1.05 | 0.89 | 11.5 | 2 | Benign |
| c.3405G>C | E1135D | N | 0.82 | 0.85 | 7.7 | 1.7 | Benign |
| c.3410A>T | Q1137L | N | 3.24 | 4.49 | 28.8 | 8.4 | Pathogenic |
| c.3427C>G | Q1143E | N | 0.96 | 1.55 | 9.8 | 1.8 | Benign |
| c.3469T>C | W1157R | F | — | — | — | — | Pathogenic |
| c.3481C>A | P1161T | W | 3.04 | 2.47 | 34.1 | 5.4 | Pathogenic |
| c.3489C>G | C1163W | F | — | — | — | — | Pathogenic |
| c.3493C>T | H1165Y | F | — | — | — | — | Pathogenic |
| c.3503T>C | V1168A | F | — | — | — | — | Pathogenic |
| c.3505A>C | I1169L | N | 1.82 | 1.27 | 26.1 | 8.9 | Pathogenic |
| c.3530A>G | I1177C | N | 2.15 | 1.97 | 24.9 | 13 | Pathogenic |
| c.3547T>A | W1183R | N | 6.65 | 2.52 | 45.9 | 38.8 | Pathogenic |
| c.3549G>T | W1183C | N | 2.51 | 4.37 | 52 | 75.3 | Pathogenic |
| c.3550A>G | T1184A | N | 2.27 | 1.73 | 28.1 | 7.8 | Pathogenic |
| c.3550A>C | T1184P | N | 2.52 | 2.57 | 29 | 37.5 | Pathogenic |
| c.3551C>G | T1184R | N | 1.12 | 0.65 | 11.5 | 1.8 | Benign |
| c.3557A>C | K1186T | N | 1.90 | 2.14 | 13.3 | 2.3 | Pathogenic |
| c.3566T>C | L1189P | N | 3.25 | 1.82 | 41.3 | 47.8 | Pathogenic |
| c.3566T>A | L1189H | N | 1.27 | 0.60 | 27.7 | 18.1 | Pathogenic |
| c.3572C>G | S1191W | N | 3.07 | 1.25 | 49.5 | 67.5 | Pathogenic |
| c.3581G>A | G1194D | W | 2.24 | 4.98 | 44.2 | 16.5 | Pathogenic |
| c.3593A>T | E1198V | W | 2.60 | 0.98 | 43.8 | 49.8 | Pathogenic |
| c.3595T>C | F1199L | F | — | — | — | — | Pathogenic |
| c.3598G>T | V1200L | N | 0.78 | 0.98 | 10.8 | 1.6 | Benign |
| c.3607C>T | R1203W | N | 1.11 | 0.78 | 12.5 | 1.7 | Benign |
| c.3616C>T | R1206C | N | 1.92 | 3.93 | 11.2 | 2.2 | Pathogenic |
Abnormal values are shown in bold type.
F, failed to express in vitro; GP, guinea pig; N, normal; W, weak (decreased) intensity of band corresponding to FH in nonreducing SDS-PAGE; –, not performed or not saturable binding (see “Individual variant datasheets” for details).
*
Normal ranges are in parentheses. HR50 refers to the concentration fold of FH mutant needed to confer 50% protection from lysis compared with the wild-type FH protein in the guinea pig hemolysis assay; BD50 refers to the concentration fold of FH mutant needed to confer similar binding to C3b compared with the wild-type FH protein (see “Methods” for details).