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. 2024 Apr 10;19(4):e0289644. doi: 10.1371/journal.pone.0289644

Table 3. Natural mutations of L->Q, I->T, F->Y in glutamate transporters (No V->T 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 I59T U->C TM1 α-helix Exposed 3 benign -
I63T U->C TM1 α-helix Exposed 2 benign uncertain
I133T U->C TM3 α-helix Exposed 4 ? damaging -
I214T U->C ECL2 loop - 1 benign uncertain (EA611)
I310T U->C ECL3 loop Exposed 5 benign -
I349T U->C IM α-helix Buried 5 damaging uncertain
I397T U->C TM7 α-helix Exposed (F9) 8 damaging -
I526T U->C Intracellular C-coil - 5 ? damaging -
EAA2 I325T U->C TM6 α-helix Exposed 2 benign -
I504T U->C Intracellular α-helix - 1 benign -
I514T U->C Intracellular α-helix - 3 benign uncertain
I522T U->C Intracellular α-helix - 2 benign -
EAA3 I72T U->C TM2 α-helix Exposed 7 benign -
I90T U->C ICL1 α-helix Buried 8 damaging uncertain
I104T U->C TM3 α-helix Exposed 4 benign uncertain (DCBXA12)
I127T U->C ECL2 loop Buried 1 ? damaging -
I271T U->C ECL3 α-helix Buried 6 benign uncertain (DCBXA12)
I298T U->C TM6 α-helix Exposed 4 benign uncertain (DCBXA12)
I304T U->C TM6 α-helix Exposed 7 ? damaging -
I307T U->C TM6 α-helix Exposed 3 benign uncertain (DCBXA12)
I391T U->C ECL4 α-helix Exposed 4 benign -
I397T U->C IM α-helix Buried 8 ? damaging -
I481T U->C Intracellular α-helix - 4 benign -
L92Q U->A ICL1 α-helix Exposed 3 damaging -
L443Q U->A TM8 α-helix Buried 8 damaging -
F50Y U->A ECL1 α-helix Exposed 5 benign benign (DCBXA12)
F508Y U->A Intracellular C-coil - 7 damaging -
EAA4 I141T U>C TM3 α-helix Exposed 5 benign -
I152T U>C TM3 α-helix Exposed 4 benign -
I282T U>C TM4 α-helix Buried 8 benign -
I374T U>C IM α-helix Exposed 4 benign -
F351Y U>A TM6 α-helix Exposed 3 benign -
VGluT1 I128T U->C TM2 α-helix - 6 benign -
VGluT2 I8T U->C Intracellular loop - - benign -
I41T U->C Intracellular β-strand - 6 benign -
I73T U->C TM1 α-helix - 6 ? damaging -
I286T U->C ICL2 α-helix Exposed 5 ? damaging -
I365T U->C TM8 α-helix Exposed 3 benign -
I369T U->C TM8 α-helix Exposed 4 benign -
I482T U->C TM12 α-helix Exposed (F9) 8 ? damaging -
VGluT3 I13T U->C Intracellular α-helix - 6 benign -
I100T U->C ECL1 α-helix - 8 damaging -
I141T U->C TM2 3/10-helix - 6 damaging -
I291T U->C ICL3 α-helix Exposed 6 damaging -
I320T U->C TM7 α-helix Buried 6 damaging uncertain
I369T U->C TM8 α-helix Exposed 3 ? damaging uncertain (DFNA2513)
I467T U->C TM11 α-helix Exposed 6 damaging -
I523T U->C Intracellular loop - 4 damaging -
YLAT2 I82T U->C TM2 α-helix Exposed 5 benign -
I115T U->C TM3 α-helix Buried 8 damaging -
I174T U->C TM4 α-helix Buried 7 ? damaging -
I204T U->C TM5 α-helix Exposed 2 benign -
I283T U->C TM7 α-helix Exposed 5 benign -
I336T U->C ICL4 α-helix Buried 6 ? damaging -
I359T U->C ICL4 β-strand Exposed (F9) 8 ? damaging -
I361T U->C ICL4 loop Exposed 4 benign -
I434T U->C TM11 α-helix Exposed 4 benign -
I441T U->C TM11 α-helix Exposed 5 benign -
I453T U->C TM12 α-helix Exposed 6 damaging -
I457T U->C TM12 α-helix Exposed 7 damaging benign
I487T U->C Intracellular α-helix - 1 benign -
F343Y U->A ICL4 α-helix Buried 5 ? damaging -
F387Y U->A TM10 α-helix Exposed 4 ? damaging -

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 glutamate 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.