Association between CFTR genotype and pancreatic insufficiency

Functional class	"Severe" CFTR mutations	"Mild" CFTR mutations
Functional class	If 2 of these mutations are present, there is a high likelihood of pancreatic insufficiency^[1,2]	If at least 1 of these mutations is present, most patients have pancreatic sufficiency^[1,2]
Class I (defective protein synthesis)	G542X W1282X R553X 621+1G>T 1717–1G>A 3120+1G>A R1162X 3659delC 1898+1G>A 2184delA 711+1G>T
Class II (abnormal processing and trafficking)	F508del I507del
Class III (defective channel regulation/gating)	G551D N1303K R560T	G85E*
Class IV (decreased channel conductance)		R117H R347P^¶ R334W^Δ
Class V (reduced synthesis and/or trafficking)		3849+10kbC>T^Δ 2789+5G>A A445E

This table shows the pancreatic phenotype for the 23 most common pathogenic mutations of the CFTR gene. The presence of 2 class I, II, or III mutations is usually associated with pancreatic insufficiency, whereas the presence of at least 1 of the class IV or V mutations listed here usually is associated with pancreatic sufficiency. Information about the pancreatic phenotype for other less common mutations is available in the references^[1,2].

CFTR: cystic fibrosis transmembrane conductance regulator gene.
* G85E is considered indeterminate for pancreatic insufficiency. In a study, 1 patient with the F508del/G85E genotype had pancreatic sufficiency and 2 patients had pancreatic insufficiency^[1].
¶ Conflicting results were found in individual patients with an R347p variant. In 2 studies that used fecal fat excretion to determine pancreatic insufficiency, all 5 patients with the F508del/R347P genotype were pancreatic-sufficient^[1,3,4]. In a separate study, the 1 patient with this genotype appeared to have pancreatic insufficiency based on a low fecal elastase level^[5].
Δ A study reported that these genotypes (R334W or 3849+10kbCT), combined with F508del or 1717–1GA, may be associated with either pancreatic insufficiency or pancreatic sufficiency (as measured by fecal elastase)^[5].

References:

Ahmed N, Corey M, Forstner G et al. Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas. Gut 2003; 52:1159.
The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org (accessed 2/3/15)
Santis G, Osborne L, Knight RA, Hodson ME. Independent genetic determinants of pancreatic and pulmonary status in cystic fibrosis. Lancet 1990; 336:1081.
Kristidis P, Bozon D, Corey M, Markiewicz D, Rommens J, Tsui LC et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992; 50:1178.
Walkowiak J, Herzig KH, Witt M, et al. Analysis of exocrine pancreatic function in cystic fibrosis: one mild CFTR mutation does not exclude pancreatic insufficiency. Eur J Clin Invest 2001; 31:796.

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Association between CFTR genotype and pancreatic insufficiency