Table 4. Natural mutations of Q->L, T->I, Y->F in glutamate transporters (No T->V mutations.
A single base mutation on the second position of the codons).
| Name | Mutation1 | 2nd base2 | Location3 | Structure4 | Exposure5 | Conservation Grade6 | Predicted Effect7 | Clinical Significance8 |
|---|---|---|---|---|---|---|---|---|
| EAA1 | T2I | C->U | Intracellular | N-coil | - | - | benign | - |
| T67I | C->U | TM1 | α-helix | Exposed | 3 | benign | - | |
| T225I | C->U | ECL2 | β-strand | - | 1 | benign | - | |
| T428I | C->U | IM | α-helix | Exposed | 7 | damaging | - | |
| EAA2 | T433I | C->U | IM | α-helix | Buried (F9) | 9 | damaging | - |
| Q152L | A->U | ECL2 | α-helix | - | 3 | benign | - | |
| EAA3 | T133I | C->U | ECL2 | loop | Exposed | 3 | ? damaging | - |
| T164I | C->U | ECL2 | β-strand | Buried (S10) | 9 | ? damaging | - | |
| T197I | C->U | ECL2 | loop | - | 4 | ? damaging | - | |
| T340I | C->U | IM | α-helix | Buried (S10) | 9 | damaging | - | |
| T364I | C->U | TM7 | α-helix | Buried (S10) | 9 | ? damaging | - | |
| T370I | C->U | TM7 | α-helix | Buried (S10) | 9 | damaging | - | |
| Y285F | A->U | ECL3 | α-helix | Buried | 8 | benign | - | |
| EAA4 | T343I | C>U | ECL3 | α-helix | Buried | 6 | benign | - |
| T366I | C>U | ICL3 | α-helix | Buried | 8 | benign | - | |
| T412I | C>U | TM7 | α-helix | Buried | 8 | damaging | - | |
| T507I | C>U | TM8 | α-helix | Buried | 5 | damaging | - | |
| Q27L | A>U | Intracellular | α-helix | - | 5 | benign | - | |
| Q549L | A>U | Intracellular | α-helix | - | 6 | ? damaging | - | |
| VGluT1 | T96I | C->U | ECL1 | β-strand | - | 3 | benign | - |
| T209I | C->U | TM5 | α-helix | Exposed | 4 | benign | - | |
| T464I | C->U | ECL5 | loop | Exposed | 7 | benign | - | |
| VGluT2 | T164I | C->U | TM3 | α-helix | - | 4 | benign | - |
| T217I | C->U | TM5 | α-helix | Exposed | 5 | benign | - | |
| VGluT3 | T40I | C->U | Intracellular | loop | - | 4 | benign | - |
| T119I | C->U | ECL1 | loop | - | 1 | benign | uncertain | |
| T305I | C->U | ICL3 | loop | Buried | 7 | damaging | - | |
| T384I | C->U | ICL4 | loop | Exposed | 7 | damaging | - | |
| T551I | C->U | Intracellular | loop | - | 5 | damaging | - | |
| YLAT2 | T10I | C->U | Intracellular | N-coil | - | - | benign | - |
| T74I | C->U | ECL1 | α-helix | Buried | 6 | ? damaging | - | |
| Q40L | A->U | Intracellular | N-coil | Exposed | 1 | benign | - |
1Protein consequence of the mutation according to HGVS numbering.
2The second base of the residue codon for the corresponding mutation.
3Topological localizations of the mutations according to transporter molecular architecture (TM = Transmembrane, ECL = Extracellular loop, IM = Intramembrane, ICL = Intracellular loop). The topological information of the mature protein obtained from Uniprot.
4Secondary structure of the corresponding residue, calculated from the determined models of native transporters available in the AlphaFold Database.
5Residue exposure according to the NACSES algorithm, predicted by ConSurf server
6Evolutionary conservation grade of the residue predicted by ConSurf server; 1 to 9, in order of increasing conservation (1 = Variable, 5 = Average, 9 = Conserved).
7Variant effect predicted by Polyphen. Benign = predicted to be benign with high confidence;? damaging = possibly damaging, predicted to be damaging with low confidence; damaging = probably damaging: predicted to be damaging with high confidence.
8Based on ClinVar’s January 21, 2023 release.
9A functional residue (exposed and highly conserved) predicted by ConSurf Server.
10A structural residue (buried and highly conserved) predicted by ConSurf Server.