Gene | Variant | Frequency (no of index patients) | Conservation | PolyPhen* | Sift† | MutPred score‡ | Previously reported | Pathogenicity | Comment | ||
Mammalia | Vertebrata | ||||||||||
C9orf72 | (GGGGCC)n, n>50–2600 | 75× | – | – | – | – | – | 22 | Likely pathogenic§ | ||
SOD1 | c.115C>G | p.L39V | 1× | Yes | No | 0.998 | 0.00 | 0.499 | 28 | Likely pathogenic§ | |
c.131A>G | p.H44R | 3× | Yes | No | 1.000 | 0.06 | 0.898 | 29 | Likely pathogenic§ | ||
c.140A>G | p.H47R | 1× | Yes | No | 0.997 | 0.00 | 0.897 | 30 | Likely pathogenic§ | ||
c.146A>G | p.H49R | 1× | Yes | No | 1.000 | 0.00 | 0.934 | 31 | Likely pathogenic | ||
c.217G>A | p.G73S | 1× | Yes | Yes | 0.970 | 0.01 | 0.669 | 32 | Likely pathogenic | ||
c.255G>C | p.L85F | 1× | Yes | Yes | 1.000 | 0.00 | 0.846 | 33 | VUS¶ | ||
c.260A>G | p.N87S | 1× | Yes | Yes | 1.000 | 0.00 | 0.692 | 34 | Likely pathogenic** | ||
c.263T>C | p.V88A | 1× | Yes | Yes | 0.999 | 0.00 | 0.786 | 31 | Likely pathogenic | ||
c.272A>C heterozygous | p.D91A | 2× | No | No | 0.000 | 0.17 | 0.485 | 35 36 | Likely pathogenic | ||
c.272A>C homozygous | p.D91A | 4× | No | No | 0.000 | 0.17 | 0.485 | 35 36 | Likely pathogenic | ||
c.301G>A | p.E101K | 1× | No | No | 0.000 | 0.61 | 0.234 | 37 38 | VUS¶ | ||
c.313A>T | p.I105F | 1× | Yes | No | 0.999 | 0.00 | 0.691 | 39 | Likely pathogenic | ||
c.326G>T | p.G109V | 1× | Yes | Yes | 1.000 | 0.00 | 0.864 | 40 | Likely pathogenic§ | ||
c.341T>C | p.I114T | 1× | Yes | No | 0.999 | 0.00 | 0.725 | 41 | Likely pathogenic** | ||
c.346C>G | p.R116G | 9× | Yes | Yes | 1.000 | 0.00 | 0.903 | 37 | Likely pathogenic§ | ||
c.400G>A | p.E134K | 1× | Yes | Yes | 1.000 | 0.17 | 0.679 | 9 | Likely pathogenic | ||
c.435G>T | p.L145F | 2× | Yes | Yes | 0.999 | 0.00 | 0.794 | 42 | Likely pathogenic | ||
c.443G>A | p.G148D | 1× | Yes | Yes | 1.000 | 0.00 | 0.955 | 43 | Likely pathogenic | ||
c.446T>C | p.V149A | 1× | Yes | Yes | 1.000 | 0.00 | 0.836 | no | VUS | ||
c.446T>G | p.V149G | 1× | Yes | Yes | 1.000 | 0.00 | 0.925 | 44 | Likely pathogenic | ||
c.449T>C | p.I150T | 1× | Yes | Yes | 0.998 | 0.00 | 0.911 | 45 | Likely pathogenic | ||
c.455T>C | p.I152T | 1× | Yes | No | 0.969 | 0.00 | 0.845 | 46 | Likely pathogenic | ||
FUS | c.1394-2delA | Direct splice site | 1× | Yes | No | – | – | – | 3 | Likely pathogenic | |
c.1432_1478del47 | p.G478Lfs*23 | 1× | – | – | – | – | – | 15 | Likely pathogenic | ||
c.1483C>T | p.R495* | 1× | – | – | – | – | – | 47 | Likely pathogenic§ | ||
c.1526G>A | p.G509D | 1× | Yes | Yes | 1.000 | 0.03 | 0.880 | 48 | Likely pathogenic | ||
c.1529A>G | p.K510R | 3× | Yes | Yes | 0.945 | 0.03 | 0.329 | 15 | Likely pathogenic§ | ||
c.1540A>G | p.R514G | 1× | No | Yes | 0.079 | 0.01 | 0.540 | 49 | Likely pathogenic§ | ||
c.1561C→T | p.R521C | 1× | Yes | No | 0.002 | 0.00 | 0.308 | 49 | Likely pathogenic§ | ||
c.1562G>A | p.R521H | 3× | Yes | No | 0.002 | 0.00 | 0.186 | 49 | Likely pathogenic§ | ||
c.1570A>G | p.R524G | 1× | Yes | Yes | 0.437 | 0.00 | 0.589 | 5 | VUS | Patient with an additional TBK1 p.Y185* and DCTN1 p.I195L variant | |
TARDBP | c.881G>T | p.G294V | 1× | Yes | No | 0.139 | 0.42 | 0.797 | 50 | Likely pathogenic | |
c.943G>A | p.A315T | 2× | Yes | Yes | 0.063 | 0.61 | 0.622 | 51 | Likely pathogenic§ | ||
c.1042G>T | p.G348C | 1× | Yes | No | 0.992 | 0.07 | 0.789 | 14 | Likely pathogenic | ||
c.1055A>G | p.N352S | 7× | Yes | No | 0.000 | 0.48 | 0.620 | 52 | Likely pathogenic** | Two patients with an additional ANXA11 p.P87T or p.G162R variant | |
c.1132_1146del15 | p.(N378_A382del) | 1× | 4/5 | 0/5 | – | – | – | No | VUS | ||
TBK1 | c.140G>A | p.R47H | 1× | Yes | Yes | 1.000 | 0.00 | 0.633 | 5 53 | VUS | |
c.358+2T>C | p.T77Wfs*3 | 1× | – | – | – | – | – | 5 53 | Likely pathogenic§ | ||
c.555T>A | p.Y185* | 1× | – | – | – | – | – | 5 53 | Likely pathogenic§ | Patient with an additional FUS p.R524G and DCTN1 p.I195L variant | |
c.1928-1930delAAG | p.E643del | 1× | Yes | Yes | – | – | – | 5 53 | Likely pathogenic | ||
OPTN | c.403G>T homozygous | p.E135* | 1× | – | – | – | – | – | No | Likely pathogenic | |
c.1320delA | p.K440Nfs*8 | 1× | – | – | – | – | – | 17 | Likely pathogenic§ | ||
CHCHD10 | c.44C>A | p.R15L | 2× | No | No | 0.993 | 0.28 | 0.380 | 54 | Likely pathogenic** | |
UBQLN2 | c.1460C>T | p.T487I | 1× | Yes | No | 0.417 | 0.24 | 0.624 | 55 | Likely pathogenic§ | |
c.1489C>T | p.P497S | 1× | No | No | 0.588 | 0.90 | 0.510 | 56 | Likely pathogenic | ||
SETX | c.1166T>C | p.L389S | 1× | Yes | Yes | 1.000 | 0.00 | 0.853 | 57 | Likely pathogenic§ | |
c.1374A>C | p.F458L | 1× | Yes | Yes | 0.999 | 0.00 | 0.696 | no | VUS | ||
c.3056C>T | p.S1019F | 1× | Yes | No | 1.000 | 0.01 | 0.667 | no | VUS | ||
c.4517A>G | p.M1506T | 1× | Yes | No | 0.999 | 0.00 | 0.821 | no | VUS | ||
c.4979T>C | p.H1660R | 1× | No | No | 0.000 | 0.74 | 0.051 | no | VUS | ||
c.5885A>G | p.H1962R | 1× | Yes | No | 1.000 | 0.03 | 0.915 | 19 | VUS | ||
NEFH | c.1376_1379delAACA | p.E459Gfs*7 | 1× | – | – | – | – | – | No | Likely pathogenic | |
c.2564_2566delAGA | p.K857del | 1× | No | No | – | – | – | No | VUS | ||
VAPB | c.166C>T | p.P56S | 1× | Yes | Yes | 1.000 | 0.00 | 0.880 | 58 59 | Likely pathogenic§ | |
VCP | c.464G>A | p.R155H | 1× | Yes | Yes | 0.849 | 0.06 | 0.798 | 60 | Likely pathogenic§ | |
ALS2†† | c.553delA homozygous | p.T185Lfs*5 | 1× | – | – | – | – | – | 20 | Likely pathogenic | |
ANXA11 | c.1087–1G>A | Direct splice site | 1× | Yes | Yes | – | – | – | No | VUS | |
c.484G>A | p.G162R | 1× | Yes | No | 0.001 | 0.38 | 0.142 | No | VUS | Patient with an additional TARDBP p.N352S variant | |
c.259C>A | p.P87T | 1× | Yes | No | 0.190 | 0.52 | 0.319 | No | VUS | Patient with an additional TARDBP p.N352S variant | |
c.137C>T | p.A46V | 1× | Yes | No | 0.125 | 0.16 | 0.334 | No | VUS | ||
c.112G>A | p.G38R | 1× | Yes | No | 1.000 | 0.51 | 0.825 | No | VUS | ||
NEK1 | c.1634A>G | p.M545T | 1× | No | No | 0.087 | 0.23 | 0.323 | No | VUS | |
c.1433C>G | p.G478A | 1× | Yes | No | 0.936 | 0.23 | 0.143 | No | VUS | ||
c.395T>C | p.Q132R | 1× | No | Yes | 1.000 | 0.04 | 0.777 | No | VUS | ||
ERBB4 | c.3809A>G | p.Q1270R | 1× | Yes | Yes | 0.421 | 0.56 | 0.709 | No | VUS | |
c.2428G>A | p.E810K | 1× | Yes | Yes | 0.999 | 0.31 | 0.710 | No | VUS | ||
c.812C>T | p.T271I | 1× | Yes | No | 0.014 | 0.35 | 0.540 | No | VUS | ||
FIG4 | c.2095C>T | p.R699C | 1× | Yes | Yes | 1.000 | 0.01 | 0.679 | No | VUS | |
c.2096G>A | p.R699H | 1× | Yes | Yes | 1.000 | 0.13 | 0.497 | No | VUS | ||
PFN1 | c.326C>T | p.T109M | 1× | No | No | 0.347 | 0.03 | 0.529 | 18 | VUS | |
SQSTM1 | c.344A>T | p.Q115L | 1× | Yes | No | 0.052 | 0.26 | 0.306 | No | VUS | |
HNRNPA1 | c.1075G>A | p.G359S | 1× | No | No | 0.957 | 0.07 | 0.461 | No | VUS | |
DCTN1 | c.583A>C | p.I195L | 1× | Yes | No | 0.001 | 0.54 | 0.089 | No | VUS | Patient with an additional TBK1 p.Y185* and FUS p.R524G variant |
For the conservation, we aligned the sequences within the Mammalia including elephant, chimpanzee, cow, mouse and platypus and within the Vertebrata including Xenopus tropicalis, zebrafish, green sea turtle, parrot and lizard. Yes, highly conserved; no, at least the amino acid in one organism is changed.
*The lower the score, the more benign the substitution.
†The Sift score ranges from 0 to 1. The amino acid substitution is predicted as damaging if the score is ≤0.05, and tolerated if the score is >0.05.
‡The MutPred pathogenicity score ranges from 0 to 1, with higher scores indicating a greater likelihood that the amino acid variation is pathogenic.
§The variant cosegregates with the disease.
¶The variant does not cosegregate with the disease, there are affected family members without that variant.
**The variant cosegregates with the disease and shows reduced penetrance.
††Mutations in ALS2 cause autosomal recessive motor neuron diseases, an autosomal-dominant inheritance has so far not been reported.
ALS, amyotrophic lateral sclerosis; HRE, hexanucleotide repeat expansion; VUS, variant of uncertain significance.