Table 1.
Described mutations in the GLA gene found in suspected FD patients
| Aminoacid change (NM_000169.2) | Nucleotide change | Exon Location | Stop Codon Position | Type of alteration | Nr. of families | Enzymatic activity (μmol/L/h) | dbSNP | HGMD | Functional Characterization (%WT) | Likely Phenotype | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Range | ||||||||||
| Pathogenic Mutations | |||||||||||
| p.Q2* | c.4C>T | 1 | 2 | Nonsense | 1 | 0.12 | rs869312313 | DM | No FC | Classical (dbFGP) | |
| p.Gly11AlafsTer110 | c.32delG | 1 | 110 | Deletion | 2 | 0.09 | 0 - 0.19 | rs1057516967 | DM | 1.8±1.4 [19] | Classical (dbFGP; HGMD) |
| p.A15E | c.44C>A | 1 | Missense | 1 | 0.06 | rs869312304 | DM | 0±0 [42] | Classical (dbFGP) | ||
| p.A15G | c.44C>G | 1 | Missense | 1 | 0.14 | No dbSNP ID | DM | 19±0.7 [36] | Classical (dbFGP) | ||
| p.G35V | c.104G>A | 1 | Missense | 1 | 0.15 | No dbSNP ID | DM | No FC | Classical (HGMD) | ||
| p.M42I | c.126G>A | 1 | Missense | 1 | 0.17 | No dbSNP ID | DM | No FC | Likely Classical (dbFGP) / Classical (HGMD) | ||
| p.W47* | c.140G>A | 1 | 47 | Nonsense | 1 | + | No dbSNP ID | DM | No FC | Classical (dbFGP) | |
| p.R49C | c.145C>T | 1 | Missense | 1 | 0.31 | No dbSNP ID | DM | 0±0 [19] | Classical (dbFGP; HGMD) | ||
| p.R49G | c.145C>G | 1 | Missense | 1 | 0 | No dbSNP ID | DM | 0±0 [19] | Classical (dbFGP) | ||
| p.R49P | c.146G>C | 1 | Missense | 1 | 0.25 | rs398123205 | DM | No FC | Classical (dbFGP; HGMD) | ||
| p.C52* | c.156C>A | 1 | 52 | Nonsense | 1 | 0.41 | No dbSNP ID | DM | No FC | Classical (dbFGP; HGMD) | |
| p.F69L | c.207C>A | 2 | Missense | 1 | + | No dbSNP ID | DM | No FC | Mild/Late-onset - cardiac variant (dbFGP; HGMD) | ||
| p.W81* | c.242G>A | 2 | 81 | Nonsense | 1 | + | rs398123208 | DM | No FC | Classical (dbFGP; HGMD) | |
| p.C94Y | c.281G>A | 2 | Missense | 2 | 0 | rs113173389 | DM | 0±0 [19] | Classical (dbFGP; HGMD) | ||
| p.R100K | c.299G>A | 2 | Missense | 1 | + | rs869312273 | DM | 0±0 [20] | Classical (dbFGP; HGMD) | ||
| p.R112C | c.334C>T | 2 | Missense | 5 | 0.25 | 0 - 1.25 | rs104894834 | DM | 0±0 [20, 42] | Classical (dbFGP; HGMD) | |
| p.R112H | c.335G>A | 2 | Missense | 3 | 0.17 | 0.03 - 0.28 | rs869312273 | DM | 0±0 [20]; 1.6±0.6 [42] | Mild proteinuria -Later-onset (dbFGP; HGMD) | |
| p.F113L | c.337T>C | 2 | Missense | 1 | 0.27 | rs869312142 | DM | 17.3±3.6 [20]; 18.3±0.8 [36] | Later onset (dbFGP); Cardiac variant (HGMD) | ||
| p.G132E | c.395G>A | 3 | Missense | 1 | 0.01 | No dbSNP ID | DM | 0±0 [42] | Classical (dbFGP) | ||
| p.C142R | c.424T>C | 3 | Missense | 2 | 0 | 0 - 0.01 | No dbSNP ID | DM | 0±0 [20, 42] | Classical (dbFGP; HGMD) | |
| p.A156D | c.467C>A | 3 | Missense | 2 | 0.16 | 0 - 0.33 | rs869312307 | DM | 0±0 [42] | Classical (dbFGP) | |
| p.C172Y | c.515G>A | 3 | Missense | 1 | 0.03 | rs869312318 | DM | 0±0 [42] | Classical (dbFGP) | ||
| p.M187T | c.560T>C | 4 | Missense | 1 | + | rs869312342 | DM | 0±0 [42] | Classical (dbFGP; HGMD) | ||
| p.C202Y | c.605G>A | 4 | Missense | 1 | + | rs869312344 | DM | 0±0 [43] | Classical (dbFGP; HGMD) | ||
| p.I198T | c.593T>C | 4 | Missense | 1 | 0.15 | rs727503950 | DM | 38.7±3.1 [43] | Later onset (dbFGP) | ||
| p.W204* | c.611G>A | 4 | 204 | Nonsense | 1 | 0.7 | rs869312346 | DM | No FC | Classical (dbFGP) | |
| p.N215S | c.644A>G | 5 | Missense | 2 | 0.34 | 0.22 - 0.47 | rs28935197 | DM | 15.6±1.0 [36] /15.7±2.4 [20] / 39.5±1.5 [43] | Later onset (dbFGP) | |
| p.R220* | c.658C>T | 5 | 220 | Nonsense | 1 | 0.06 | rs727503949 | DM | 0±0 [43] | Classical (dbFGP) | |
| p.W226* | c.677G>A | 5 | 226 | Nonsense | 1 | 0.48 | rs398123219 | DM | No FC | Classical (dbFGP) | |
| p.R227* | c.679C>T | 5 | 227 | Nonsense | 3 | 0.08 | 0.06 - 0.11 | rs104894841 | DM | No FC | Classical (dbFGP; HGMD) |
| p.R227Q | c.680G>A | 5 | Missense | 1 | 0 | rs104894840 | DM | 0±0 [20, 42] | Classical (dbFGP; HGMD) | ||
| p.Lys240Glufs*9 | c.718_719delAA | 5 | 248 | Deletion | 1 | 0.01 | No dbSNP ID | DM | No FC | Classical (dbFGP) | |
| p.M267I | c.801G>A | 5 | Missense | 1 | 0.17 | rs869312408 | DM | No FC | Classical (dbFGP; HGMD) | ||
| p.V269M | c.805G>A | 6 | Missense | 1 | + | rs869312427 | DM | 0±0 [43] | Classical dbFGP; HGMD) | ||
| p.V269A | c.806T>C | 6 | Missense | 1 | 0.41 | rs28935488 | DM | 9.0±1.4 [42] | Classical (dbFGP; HGMD) | ||
| p.T282I | c.845C>T | 6 | Missense | 1 | 0.05 | No dbSNP ID | DM | 5.0±0.5 [42] / 5.2±0.2 [36] | Classical (dbFGP) | ||
| p.M290I | c.870G>A | 6 | Missense | 10 | 0.31 | 0 - 0.60 | rs869312438 | DM | 39±1.8 [42] | Later onset (dbFGP) - Classical (HGMD) | |
| p.A292V | c.875C>T | 6 | Missense | 1 | 0.54 | No dbSNP ID | DM | No FC | Classical (dbFGP) | ||
| p.P293S | c.877C>T | 6 | Missense | 1 | 0.10 | rs869312440 | DM | No FC | Classical (dbFGP) | ||
| p.R301G | c.901C>G | 6 | Missense | 1 | 0,34 | rs398123224 | DM | 19±4.1 [42] | VUS (dbFGP) | ||
| p.R301* | c.901C>T | 6 | 301 | Nonsense | 2 | 0.06 | 0.01 – 0.11 | rs398123224 | DM | No FC | Classical (dbFGP) - Kidney disease (HGMD) |
| p.Gln333Glufs*14 | c.996_999delACAG | 6 | 346 | Deletion | 2 | 1.84 | rs398123229 | DM | No FC | Classical (dbFGP; HGMD) | |
| p.R342Q | c.1025G>A | 7 | Missense | 4 | 0.07 | 0 -0.14 | rs28935493 | DM | 0±0 [20, 42] | Classical (dbFGP) | |
| p.Ser345Argfs*29 | c.1033_1034delTC | 7 | 373 | Deletion | 2 | 0.21 | rs398123198 | DM | No FC | Classical (dbFGP) | |
| p.W349* | c.1046G>A | 7 | 349 | Nonsense | 1 | 0,45 | No dbSNP ID | DM | No FC | Classical (dbFGP) | |
| p.R356W | c.1066C>T | 7 | Missense | 17 | 0.47 | 0.19 - 1.62 | rs104894827 | DM | 16.9±2.3 [42] | Later onset (dbFGP) | |
| p.R363H | c.1088G>A | 7 | Missense | 3 | 0.43 | 0.13 - 0.72 | rs111422676 | DM | 31.9±2.9 [42] | Later onset (dbFGP) - Renal presentation (HGMD) | |
| p.Y365* | c.1095T>A | 7 | 365 | Nonsense | 3 | 0.06 | 0 - 0.13 | rs104894849 | DM | No FC | Classical (dbFGP) |
| p.W399* | c.1196G>A | 7 | 399 | Nonsense | 1 | + | No dbSNP ID | DM | 2% [21] | Classical (dbFGP; HGMD) | |
| p.Thr412Serfs*? | c.1235_1236delCT | 7 | late termination codon | Deletion | 1 | 0 | rs797044777 | DM | No FC | Classical (dbFGP; HGMD) | |
| Variants of Unknown Significance | |||||||||||
| p.E66Q | c.196G>C | 2 | Missense | 1 | + | rs104894833 | DFP | 52.0±1.3 [36] | Benign (dbFGP) | ||
| p.R118C | c.352C>T | 2 | Missense | 30 | 1.68 | 1.15 - 2.10 | rs148158093 | DM | 24.0±1.3 [36] | Benign (dbFGP); Cardiac variant (HGMD) | |
| p.A143T | c.427G>A | 3 | Missense | 8 | 1.04 | 0.58 - 1.86 | rs104894845 | DM | 31.3±5.6 [42] | Benign (dbFGP) | |
| p.R220Q | c.659G>A | 5 | Missense | 1 | 1.17 | rs727503949 | DM? | 104±11.3 [42] | Likely bening (dbFGP) | ||
| p.N228S | c.683A>G | 5 | Missense | 1 | 2.03 | rs869312152 | DM | 59.5±9.8 [43] / 124.5±4.1 [36] | Likely benign (dbFGP) | ||
| p.D313Y | c.937G>T | 6 | Missense | 38 | 1.65 | 0.72 - 2.10 | rs28935490 | DM? | 83.9±21.1 [42] | Benign (dbFGP) | |
| p.R356Q | c.1067G>A | 7 | Missense | 1 | 0.9 | rs869312163 | DM | 89.1±5.0 [42] / 36.1±1.5 [36] | Later onset (dbFGP) | ||
| p.A368T | c.1102G>A | 7 | Missense | 1 | 1.69 | 1.69 | rs144994244 | DM? | 103.7±33.6 [42] | Benign (dbFGP) | |
F Female, M Male, No FC No functional characterization, NA Not Applicable, VUS Variant of Unknown Significance, DM Disease Causing Mutation, DM? Disease Causing Mutation?, DFP disease-associated polymorphism with supporting functional evidence, dbFGP (International Fabry Disease Genotype-Phenotype Database http://dbfgp.org/dbFgp/fabry/); DBS enzymatic activity applicable only for male: for samples screened by LEIM-UNIFESP the result is show as μmol/L/h; for samples screened by other laboratories, the result is show as + (positive)