Table 3.
Pathogenicity predictions for FH variants and their classification based on expression and functional data
| Transcript | Protein | FH domain | CADD score | Classification | Discrepancy | AF (gnomAD) | |
|---|---|---|---|---|---|---|---|
| Predicted | Observed | ||||||
| N-terminal region (CADD score cutoff = 19) | |||||||
| c.5G>C | R2T | SP | 6.11 | Benign | Benign | No | 2 × 10−5 |
| c.32T>C | M11T | SP | 15.48 | Benign | Benign | No | NP |
| c.157C>T | R53C* | SCR1 | 24.4 | Pathogenic | Pathogenic | No | 2 × 10−5 |
| c.184G>A | V62I* | SCR1 | 7.108 | Benign | Benign | No | 3 × 10−1 |
| c.220C>T | L74F | SCR1 | 13.00 | Benign | Benign | No | 4 × 10−6 |
| c.232A>G | R78G* | SCR1 | 19.92 | Pathogenic | Pathogenic | No | NP |
| c.242A>C | Q81P | SCR1 | 22.1 | Pathogenic | Pathogenic | No | NP |
| c.245A>G | K82R | SCR2 | 22.1 | Pathogenic | Benign | Yes† | 2 × 10−5 |
| c.272C>G | T91S | SCR2 | 19.90 | Pathogenic | Benign | Yes† | 8 × 10−6 |
| c.332T>A | V111E | SCR2 | 26.3 | Pathogenic | Benign | Yes† | 1 × 10−4 |
| c.400T>C | W134R | SCR2 | 27.2 | Pathogenic | Pathogenic‡ | No | NP |
| c.451G>A | A151T | SCR3 | 3.283 | Benign | Benign | No | 4 × 10−6 |
| c.472G>A | V158I | SCR3 | 0.001 | Benign | Benign | No | 1 × 10−4 |
| c.476G>A | S159N | SCR3 | 16.65 | Benign | Benign | No | 4 × 10−5 |
| c.481G>T | A161S | SCR3 | 11.90 | Benign | Benign | No | 9 × 10−5 |
| c.484A>G | M162V | SCR3 | 0.017 | Benign | Benign | No | 3 × 10−5 |
| c.497G>T | R166L | SCR3 | 17.01 | Benign | Pathogenic | Yes§ | 7 × 10−6 |
| c.524G>C | R175P * | SCR3 | 7.153 | Benign | Pathogenic | Yes§ | 4 × 10−6 |
| c.560A>T | D187V | SCR3 | 17.14 | Benign | Benign | No | NP |
| c.592T>C | W198R | SCR3 | 24.2 | Pathogenic | Pathogenic | No | NP |
| c.595A>G | S199G | SCR3 | 24.5 | Pathogenic | Pathogenic | No | NP |
| c.647T>C | I216T | SCR4 | 0.001 | Benign | Benign | No | 1 × 10−4 |
| c.653G>A | G218E * | SCR4 | 24.7 | Pathogenic | Pathogenic‡ | No | NP |
| c.661A>G | I221V | SCR4 | 0.001 | Benign | Benign | No | 2 × 10−5 |
| c.773C>T | P258L | SCR4 | 21.1 | Pathogenic | Pathogenic | No | 4 × 10−6 |
| Midregion (CADD score cutoff = 19) | |||||||
| c.908G>A | R303Q | SCR5 | 0.169 | Benign | Benign | No | 2 × 10−5 |
| c.974G>A | C325Y | SCR6 | 25.7 | Pathogenic | Pathogenic‡ | No | NP |
| c.1022G>A | R341H | SCR6 | 7.702 | Benign | Benign | No | 4 × 10−5 |
| c.1064A>C | Y355S | SCR6 | 22.2 | Pathogenic | Pathogenic‡ | No | NP |
| c.1189G>A | G397R * | SCR7 | 28.8 | Pathogenic | Pathogenic‡ | No | NP |
| c.1198C>A | Q400K * | SCR7 | 0.019 | Benign | Benign‡ | No | 1 × 10−4 |
| c.1204C>A | H402Y * | SCR7 | 0.001 | Benign | Benign | No | 7 × 10−1 |
| c.1231T>A | S411T * | SCR7 | 0.158 | Benign | Benign | No | NP |
| c.1292G>A | C431Y * | SCR7 | 24.3 | Pathogenic | Pathogenic‡ | No | NP |
| c.1343G>A | C448Y * | SCR8 | 23.0 | Pathogenic | Pathogenic‡ | No | NP |
| c.1424A>C | Y475S * | SCR8 | 20.3 | Pathogenic | Benign‡ | Yes† | NP |
| c.1507C>G | P503A | SCR8 | 21.9 | Pathogenic | Benign | Yes† | 2 × 10−5 |
| c.1548T>A | N516K | SCR9 | 21.7 | Pathogenic | Benign | Yes† | 3 × 10−4 |
| c.1565A>G | D522G | SCR9 | 13.10 | Benign | Benign | No | NP |
| c.1591A>G | T531A | SCR9 | 0.029 | Benign | Benign | No | 8 × 10−6 |
| c.1652T>C | I551T | SCR9 | 21.4 | Pathogenic | Benign | Yes† | 5 × 10−3 |
| c.1745G>A | R582H | SCR10 | 17.71 | Benign | Benign | No | 2 × 10−5 |
| c.1825G>A | V609I | SCR10 | 0.768 | Benign | Benign | No | 2 × 10−4 |
| c.1922T>C | V641A | SCR11 | 13.51 | Benign | Benign | No | 5 × 10−5 |
| c.1949G>T | G650V | SCR11 | 0.184 | Benign | Benign | No | 2 × 10−4 |
| c.2056G>A | V686M | SCR11 | 34 | Pathogenic | Benign | Yes† | NP |
| c.2120C>T | P707L | SCR12 | 25.1 | Pathogenic | Benign | Yes† | NP |
| c.2461C>T | H821Y | SCR14 | 0.107 | Benign | Benign | No | 9 × 10−5 |
| c.2503G>T | V835L | SCR14 | 0.460 | Benign | Benign | No | 1 × 10−5 |
| c.2650T>C | S884P | SCR15 | 12.28 | Benign | Benign | No | 3 × 10−5 |
| c.2695T>G | Y899D * | SCR15 | 23 | Pathogenic | Pathogenic‡ | No | NP |
| c.2850G>T | Q950H * | SCR16 | 14.17 | Benign | Benign | No | 3 × 10−3 |
| c.2851T>C | Y951H | SCR16 | 14.6 | Benign | Benign | No | 1 × 10−5 |
| c.2867C>T | T956M * | SCR16 | 14.99 | Benign | Benign | No | 1 × 10−3 |
| c.2879T>C | F960S | SCR16 | 0.012 | Benign | Benign | No | 6 × 10−5 |
| c.2918G>A | C973Y * | SCR16 | 22.8 | Pathogenic | Pathogenic‡ | No | NP |
| c.3050C>T | T1017I | SCR17 | 10.49 | Benign | Benign | No | 1 × 10−3 |
| c.3062A>T | Y1021F | SCR17 | 0.842 | Benign | Benign | No | NP |
| c.3079G>C | A1027P | SCR17 | 0.004 | Benign | Benign | No | 6 × 10−5 |
| c.3148A>T | N1050Y * | SCR18 | 14.17 | Benign | Benign | No | 1 × 10−2 |
| c.3160G>A | V1054I | SCR18 | 16.12 | Benign | Benign | No | 5 × 10−5 |
| c.3172T>C | Y1058H | SCR18 | 0.001 | Benign | Benign | No | 6 × 10−4 |
| c.3176T>C | I1059T | SCR18 | 12.6 | Benign | Benign | No | 7 × 10−3 |
| c.3178G>C | V1060L | SCR18 | 0.019 | Benign | Benign | No | 5 × 10−4 |
| c.3179T>C | V1060A | SCR18 | 1.253 | Benign | Benign | No | NP |
| c.3181T>C | S1061P | SCR18 | 4.836 | Benign | Benign | No | NP |
| c.3226C>G | Q1076E | SCR18 | 3.884 | Benign | Benign | No | 3 × 10−4 |
| c.3231T>G | C1077W * | SCR18 | 23.2 | Pathogenic | Pathogenic‡ | No | NP |
| c.3234G>T | R1078S | SCR18 | 3.369 | Benign | Benign | No | 7 × 10−5 |
| c.3264A>C | E1088D | SCR18 | 18.53 | Benign | Benign | No | NP |
| C-terminal region (CADD score cutoff: 10) | |||||||
| c.3355G>A | D1119N * | SCR19 | 24.4 | Pathogenic | Pathogenic | No | NP |
| c.3356A>G | D1119G * | SCR19 | 23 | Pathogenic | Pathogenic | No | 4 × 10−6 |
| c.3357C>G | D1119E | SCR19 | 11.94 | Pathogenic | Pathogenic | No | 1 × 10−5 |
| c.3389C>T | P1130L | SCR19 | 15.04 | Pathogenic | Benign | Yes† | NP |
| c.3405G>C | E1135D | SCR19 | 15.16 | Pathogenic | Benign | Yes† | 4 × 10−6 |
| c.3410A>T | Q1137L | SCR19 | 16.39 | Pathogenic | Pathogenic | No | NP |
| c.3425A>G | Y1142C * | SCR19 | 22.1 | Pathogenic | Pathogenic | No | NP |
| c.3427C>G | Q1143E | SCR19 | 0.001 | Benign | Benign | No | 9 × 10−3 |
| c.3454T>A | C1152S * | SCR19 | 23.6 | Pathogenic | Pathogenic‡ | No | 4 × 10−6 |
| c.3469T>C | W1157R | SCR19 | 26.5 | Pathogenic | Pathogenic‡ | No | NP |
| c.3481C>A | P1161T | SCR19 | 23.6 | Pathogenic | Pathogenic‡ | No | NP |
| c.3489C>G | C1163W | SCR19 | 25.6 | Pathogenic | Pathogenic‡ | No | NP |
| c.3493C>T | H1165Y | SCR19 | 11.20 | Pathogenic | Pathogenic‡ | No | 2 × 10−5 |
| c.3497C>T | P1166L * | SCR20 | 13.96 | Pathogenic | Pathogenic | No | NP |
| c.3503T>C | V1168A | SCR20 | 19.03 | Pathogenic | Pathogenic‡ | No | NP |
| c.3505A>C | I1169L | SCR20 | 15.43 | Pathogenic | Pathogenic | No | NP |
| c.3530A>G | Y1177C | SCR20 | 22.8 | Pathogenic | Pathogenic | No | NP |
| c.3547T>A | W1183R | SCR20 | 19.26 | Pathogenic | Pathogenic | No | NP |
| c.3549G>T | W1183C | SCR20 | 22.5 | Pathogenic | Pathogenic | No | NP |
| c.3550A>G | T1184A | SCR20 | 0.502 | Benign | Pathogenic | Yes§ | NP |
| c.3550A>C | T1184P | SCR20 | 1.498 | Benign | Pathogenic | Yes§ | NP |
| c.3551C>G | T1184R | SCR20 | 0.001 | Benign | Benign | No | NP |
| c.3557A>C | K1186T | SCR20 | 0.255 | Benign | Pathogenic | Yes§ | 4 × 10−6 |
| c.3566T>C | L1189P | SCR20 | 15.81 | Pathogenic | Pathogenic | No | NP |
| c.3566T>A | L1189H | SCR20 | 20.3 | Pathogenic | Pathogenic | No | NP |
| c.3572C>T | S1191L* | SCR20 | 12.98 | Pathogenic | Pathogenic | No | NP |
| c.3572C>G | S1191W | SCR20 | 17.31 | Pathogenic | Pathogenic | No | NP |
| c.3581G>A | G1194D | SCR20 | 15.28 | Pathogenic | Pathogenic‡ | No | 1 × 10−5 |
| c.3593A>T | E1198V | SCR20 | 22.3 | Pathogenic | Pathogenic‡ | No | NP |
| c.3595T>C | F1199L | SCR20 | 21.8 | Pathogenic | Pathogenic‡ | No | NP |
| c.3598G>T | V1200L | SCR20 | 0.001 | Benign | Benign | No | NP |
| c.3607C>T | R1203W | SCR20 | 0.005 | Benign | Benign | No | 4 × 10−5 |
| c.3616C>T | R1206C | SCR20 | 0.144 | Benign | Pathogenic | Yes§ | NP |
| c.3628C>T | R1210C* | SCR20 | 2.952 | Benign | Pathogenic | Yes§ | 1 × 10−4 |
| c.3644G>A | R1215Q* | SCR20 | 15.74 | Pathogenic | Pathogenic | No | NP |
FH variants with allele frequency >.0001 in whole gnomAD are in bold type.
NP, not present.
*
FH variant that was characterized in a previous study.
†
Predicted pathogenic and found benign.
‡
Variant that is not expressed or likely not expressed in vivo.
§
Predicted benign and found pathogenic.