Table 1.

Effect of complex alleles on the effectiveness of targeted therapy.

#	Complex Allele	Pathogenicity of Variants	Impact on the Development and Severity of CF	Genotype	Efficacy of Targeted Therapy	Epidemiology	Links
1	[R117H;TG12T5]	Both cause CFTR-RD	Cause CFTR-RD	Non-CF	Not enough information	Caucasian	[13,34]
2	[R117L; L997F]	R117L may cause CFTR-RD	Yes Increase each other’s pathogenicity	Mild	Not enough information	Not enough information	[40]
3	[R334W;R1158X]	Both cause CF	Not enough information	Severe genotype in trans with F508del	Not enough information	Portuguese	[31]
4	[I148T;G378X]	I148T does not cause CF	Not enough information	Severe genotype in trans with L867X	Not enough information	Caucasian	[12]
5	[I148T;9T;3199del6]	I148T does not cause CF, the other two cause CF	Insufficient clinical data and follow-up period	Severe genotype in trans with Class 1–3 mutations	Not enough information	American	[47]
6	[L467F;F508del]	L467F polymorphism	Does not affect	Severe genotype in trans with F508del	Lum+Iva for L467F;F508del/F508del–no; ETI for L467F;F508del/F508del–yes	Russian	[21]
7	[L467F;F508del]	L467F polymorphism	Does not affect	Severe genotype in trans with F508del	Lum+Iva for L467F;F508del/F508del–no	French	[55]
8	[L467F;F508del]	L467F polymorphism	Not enough information	Severe genotype in trans with Class 1 mutations	ETI for L467F;F508del/class 1–no	Italian	[57]
9	[F87L;F508del;I1027T]	F87L, I1027T–polymorphism	Yes Increase each other’s pathogenicity	Severe genotype in trans with F508del	Lum for F87L;F508del;I1027T/F508del–no	French	[54]
10	[R347H;D979A]	Both cause CF	Yes Increase each other’s pathogenicity	Severe genotype in trans with F508del	Not enough information	Not enough information	[38,39]
11	[E474K;F508del]	E474K-varying clinical consequence	Yes Increase each other’s pathogenicity	Severe genotype in trans with c.3158_3468+3219del	Not enough information	Albanian	[46]
12	[F508del;R553Q]	R553Q-Variant of unknown clinical significance	Does not affect	Depending on the version in trans position	Not enough information	German	[58]
13	[G576A;R668C]	Both CFTR-RD-causing	Yes Increase each other’s pathogenicity	Mild	Not enough information	French	[27]
14	[D443Y;G576A;R668C]	All CFTR-RD-causing	Yes Increase each other’s pathogenicity	Mild	Not enough information	French	[27]
15	[G149R; G576A;R668C]	All CFTR-RD-causing	Yes Increase each other’s pathogenicity	Severe genotype in trans with Class 1–3 mutations	Not enough information	French	[27]
16	[S466X(TGA);R1070Q]	Both cause CF	Does not affect	Severe genotype in trans with Class 1–3 mutations	Lum+Iva and ETI for S466X(TGA);R1070Q/CFTRdele2,3-no	Russian	[23,24]
17	[Arg74Trp;Val201Met;Asp1270Asn]	All CFTR-RD-causing	Yes Increase each other’s pathogenicity	Mild	Not enough information	German-Moroccan	[37]