Table 2.
Predicted pathogenicity of selected EPM2A missense mutations
| PolyPhen-2 |
CUPSAT |
SDM |
|||||
|---|---|---|---|---|---|---|---|
| Probability score | Prediction | ΔΔG (kcal/mol) | Predicted overall stability | ΔΔG (kcal/mol) | Outcome | ||
| F5S | Lafora Epilepsy Mutation Database(Ianzano et al., 2005) | 0.198 | Benign | −4.045 | Destabilizing | −2.96 | Reduced stability |
| V7A | Salar et al. (2012) | 0.092 | Benign | −6.71 | Destabilizing | −2.71 | Reduced stability |
| S25P | Ganesh et al. (2002) | 1 | Probably damaging | 0.56 | Stabilizing | −0.78 | Reduced stability |
| E28K | (Minassian et al., 2000) Current report |
1 | Probably damaging | −0.76 | Destabilizing | −1.09 | Reduced stability |
| W32G | (Minassian et al., 2000) Current report |
1 | Probably damaging | −0.595 | Destabilizing | 2.76 | Increased stability |
| E56K | Lesca et al. (2010) | 1 | probably damaging | 2.605 | Stabilizing | −0.87 | Reduced stability |
| F84L | Gomez-Garre et al. (2000) | 0.003 | Benign | −2.705 | Destabilizing | −1.89 | Reduced stability |
| Y86D | Jara-Prado et al. (2014) | 0.863 | Possibly damaging | −1.68 | Destabilizing | −2.77 | Reduced stability |
| K87T | Lesca et al. (2010) | 1 | Probably damaging | −0.26 | Destabilizing | −0.63 | Reduced stability |
| R91P | Ianzano et al. (2004) | 0.988 | Probably damaging | −0.145 | Destabilizing | −1.26 | Reduced stability |
| R108C | Ganesh et al. (2002) and Minassian et al. (2000) | 1 | Probably damaging | 1.31 | Stabilizing | −0.28 | Reduced stability |
| K140N | Singh et al. (2008) | 0.915 | Possibly damaging | −1.975 | Destabilizing | −0.86 | Reduced stability |
| N148Y | Singh et al. (2008) | 0.085 | Benign | 0 | No effect | 1.21 | Increased stability |
| T187A | Ki et al. (2003) | 0.999 | Probably damaging | −1.06 | Destabilizing | 0.06 | Increased stability |
| A188G | Singh and Ganesh (2009) | 1 | Probably damaging | −5.965 | Destabilizing | −0.92 | Reduced stability |
| E210K | Singh et al. (2008) | 0.381 | Benign | 0.28 | Stabilizing | −0.04 | Reduced stability |
| P211L∗ | Lafora Epilepsy Mutation Database (Ianzano et al., 2005) | 0.867 | Possibly damaging | −1.74 | Destabilizing | −0.58 | Reduced stability |
| E224I | Ganesh et al. (2002) | 0.812 | Possibly damaging | 0.585 | Stabilizing | −0.57 | Reduced stability |
| G240S | Gomez-Garre et al. (2000) | 0.815 | Possibly damaging | 1.11 | Stabilizing | −0.01 | Reduced stability |
| P246A | Singh and Ganesh (2009) | 0.985 | Probably damaging | −2.71 | Destabilizing | 2.19 | Increased stability |
| G279C∗ | (Jara-Prado et al., 2014) Current report |
1 | Probably damaging | −1.76 | Destabilizing | −0.01 | Reduced stability |
| G279S∗ | Franceschetti et al. (2006), Gomez-Garre et al. (2000), Minassian et al. (2000) and Serratosa et al. (1999) | 1 | Probably damaging | −1.73 | Destabilizing | −2.32 | Reduced stability |
| Y294N | Gomez-Garre et al. (2000) and Serratosa et al. (1999) | 0.999 | Probably damaging | 1.44 | Stabilizing | −2.3 | Reduced stability |
| P301L | Gomez-Garre et al. (2000) | 1 | Probably damaging | −4.335 | Destabilizing | 1.26 | Increased stability |
| L310W | Singh et al. (2008) | 1 | Probably damaging | −2.275 | Destabilizing | −1.24 | Reduced stability |
| F321C∗∗ | Lynch et al. (2016) | 1 | Probably damaging | −2.5 | Destabilizing | −0.19 | Reduced stability |
Mutations explicitly associated with a slow or late-onset phenotype in the compound heterozygous state are indicated by (∗) or in the homozygous state by (∗∗), according to the Lafora Epilepsy Mutation Database (http://projects.tcag.ca/lafora/), the indicated reference, or the current study. For CUPSAT results, ΔΔG was predicted for residues in both subunits of the laforin structure (chains A and C from PDB:4rkk); values shown represent an average. Green indicates benign or stabilizing (≥0 in CUPSAT or SDM); orange indicates possibly damaging or destabilizing (between −2 and 0 in CUPSAT or SDM); red indicates probably damaging or destabilizing (<−2 in CUPSAT or SDM).