TABLE 3

List of confidence-graded mutations associated with phenotypic drug resistance as determined by best confidence values

Drug (phenotypic testing)GeneHigh-confidence mutationsModerate-confidence mutationsMinimal-confidence mutationsNo association with resistance
First-line 
 Rifampicin (R)rpoBF505V+D516Y, S512T, Q513H+L533P, Q513-F514ins, Q513K, Q513L, Q513P, F514dupl, M515I+D516Y, D516A, D516F, D516G, D516G+L533P, D516ins, D516N, D516V, Del N518, S522Q, H526C, H526D, H526F, H526G, H526L, H526R, H526Y S531F, S531L, S531Q, S531W, S531Y, D626ED516Y, S522L, H526P, L533PL511P, H526N, I572F
 Isoniazid (H)inhA-mabAg-102a#,¶c-15tg-102a#,¶, t-80g, g-47c, T4I
katGS315I, S315N, S315T, pooled frameshifts and premature stop codonsA110V, R463L, L499M
furAL68F
mshAA187V#,¶N111S
Second-line (group A) 
 Moxifloxacin (MFX)gyrAG88C, A90V, S91P, D94A, D94G, D94N, D94YE21Q, S95T, G247S, G668D, V712L
 Ofloxacin (OFX)/levofloxacin (LFX)gyrAG88A, G88C, S91P, A90V, D94A, D94G, D94H, D94N, D94YD89NE21Q, T80A, S95T, G247S, G668D, V712L
gyrBE459K, A504V
Second-line (group B) 
 Amikacin (AM)rrsa1401g, g1484t
 Kanamycin (KM)eisc-14t, g-10ag-37t, c-12ta1338c
rrsa514c#, a1401g, c1402t, g1484t
rrs+eisrrs c517t# + eis g-37t
 Capreomycin (CM)rrsa1401g, c1402t, g1484tc517t
tlyAN236K, pooled frameshifts and premature stop codonsD149H
 Streptomycin (S)rpsLK43R, K43T, K88Q, K88R, T40I
rrsa1401g#, a514c, a514t, c462t, c513t, c517t
gidBE92D#,¶L16R, V110G, pooled frameshifts and premature stop codons
Second-line (group C) 
 Ethionamide and prothionamide (ETO/PTO) inhAc-15t+I194T, c-15t+S49Ac-15t
ethAQ347Stop
Second-line (group D) 
 Pyrazinamide (Z)pncAt-12c, a-11g, t-7c, A3E, L4S, I6T, V7G, D8E, D8G, D8N, Q10P, D12A, D12N, C14R, G17D, L19P, G24D, Y34D, A46V, K48T, D49G, D49N, H51Q, H51R, P54S, H57D, H57P, H57R, H57Y, S59P, P62L, P62Q, D63G, S66P, S67P, W68C, W68R, H71D, H71Q, H71Y, C72R, T76P, H82R, L85P, L85R, F94L, F94S, K96N, K96R, G97C, G97D, G97S, Y103H, S104R, G108R, L116P, L116R, L120P, R123P, V125F, V125G, V128G, G132A, G132D, G132S, A134V, T135N, T135P, H137P, C138Y, V139G, V139L, Q141P, T142A, T142K, T142M, indel - R148ins (inframe), L151S, V155G, L159P, T160P, G162D, T168P, L172P, M175T, M175V, V180F, V180G, Pooled frameshifts and premature stop codonsV7G, Q10R, P54L, W68G, K96E, K96T, A171E, M175ID12G, F58L, H71R, I133T, V139Aindel - c-125del, I31T, L35R, T47A, I6L, K48T, T114M

The table includes all the mutations graded according to the proposed standardised approach for providing confidence levels to their association with phenotypic drug resistance. Standard type represents associations based on nominal p-values (putative); bold type represents associations based on corrected p-values. The rationale for pooling insertions/deletions and nonsense mutations can be found in online supplementary material 5. Tables 1 and 2 provide the details of the data included in the grading system and the definitions for the confidence categories. Indeterminate mutations were not included in the table and can be found in online supplementary material 8. Drugs were classified based on the updated guidelines for short and individualised regimens [4]. #: six associations were not considered for further analysis as there was probably no causative relationship between these genetic changes and the resistance to the antibiotic in question; : genotype-specific mutation.