ABCMdb

PMID: 23974870

Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.
Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25., [PubMed]

Sentences

No. Mutations Sentence Comment

112 ABCC7 p.Arg1070Gln ABCC7 p.Leu558Ser ABCC7 p.Gln359Lys dVariants p.[Gln359Lys; Thr360Lys], p.Leu558Ser and p.Arg1070Gln. Login to comment 118 ABCC7 p.His199Tyr Of the four variants for which we did not measure chloride conduction, one (p.His199Tyr) exhibited a severe processing defect in HeLa cells (<0.01) and was categorized as functionally deficient (Fig. 3). Login to comment 119 ABCC7 p.Arg1070Gln ABCC7 p.Leu558Ser ABCC7 p.Thr360Lys ABCC7 p.Gln359Lys The remaining three variants (p.[Gln359Lys; Thr360Lys], p.Leu558Ser and p.Arg1070Gln) exhibited processing greater than 10% of that of wild-type CFTR and were not functionally classified. Login to comment 137 ABCC7 p.Val754Met ABCC7 p.Asp1270Asn ABCC7 p.Arg75Gln ABCC7 p.Arg1070Gln ABCC7 p.Ser1235Arg ABCC7 p.Asp1152His ABCC7 p.Tyr569Asp ABCC7 p.Phe1052Val ABCC7 p.Arg668Cys ABCC7 p.Arg31Cys ABCC7 p.Leu997Phe ABCC7 p.Ile1027Thr ABCC7 p.Arg1162Leu ABCC7 p.Arg1070Trp ABCC7 p.Thr360Lys ABCC7 p.Ser977Phe ABCC7 p.Gln359Lys ABCC7 p.Asp614Gly ABCC7 p.Asp579Gly ABCC7 p.Leu227Arg In addition to these ten variants, c.1210-12(7) (legacy name 7T) had already been reported to be non-penetrant48 and was identified as a second variant in numerous fathers, and a twelfth variant, p.Ile1027Thr, was deemed 159 variants ࣙ0.01% frequency in CFTR2 127 variants meet clinical and functional criteria Clinical and functional analysis 13 variants meet neither criteria 14 variants 5 variants 7 variants 6 variants Evidence of non-penetrance No evidence of non-penetrance 19 variants meet clinical or functional criteria 127 variants are CF causing 12 variants are non CF causing 20 variants are indeterminate p.Arg117HisߤC p.Arg75Gln p.Gly576Alaߤ p.Arg668Cys ߤ p.Met470Val C p.IIe1027Thr ߤC p.Val754Met ߤC p.IIe148Thr ߤC p.Arg31Cys C p.Ser1235Arg ߤ p.Leu997Phe ߤ p.Arg1162Leu p.Leu227Arg F p.Gln525* F p.Leu558SerC p.Asp614Gly C c.2657+2_2657+3insA C c.1418delG F c.1210-12(7) ߤ p.Arg1070Gln C p.Asp1270Asn ߤC p.[Gln359Lys; Thr360Lys] p.Gly1069Argߤ p.Asp1152His p.Phe1052Val c.1210-12(5) p.Arg74Trpߤ p.IIe1234Val ߤC p.Arg1070Trp ߤF p.Ser977Phe F p.Asp579Gly C p.Tyr569Asp F Penetrance analysis Figure 4ߒ Assignment of disease liability to the 159 most frequent CFTR variants using three criteria. Login to comment 147 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Asp1152His Included among the variants meeting neither clinical nor functional criteria are those that have previously been associated with variable penetrance (such as p.Asp1152His), variants that have been reported as part of complex alleles in which the disease liability of each variant individually could not be determined (such as the pair p.Arg74Trp and p.Asp1270Asn) and variants with incomplete clinical or functional analysis. Login to comment 173 ABCC7 p.Val754Met ABCC7 p.Arg75Gln ABCC7 p.Ser1235Arg ABCC7 p.Arg31Cys ABCC7 p.Leu997Phe ABCC7 p.Arg1162Leu The 127 variants that met both clinical and functional criteria were designated cystic fibrosis causing; however, 32 remaining -variants Table 1ߒ Variants associated with incomplete penetrance Variant Number of alleles in CFTR2 Frequency in CFTR2 (out of 70,777 known alleles) Number that occur in trans with a CF-causing variant in fathers Number reported in 2,062 fathers Frequency in fathers (out of 4,124 alleles) Allele frequency in 1000 Genomes Project Variants that met clinical criteria but did not meet functional criteria p.Arg31Cys 13 0.00018 4 4 0.00097 0.001-0.004 p.Ile148Thra 99 0.00140 4 9 0.00218 Not available p.Met470Val 41 0.00058 Not analyzed 1,412 0.34239 0.087-0.647 p.Val754Met 9 0.00013 4 7 0.00170 0-0.003 Variants that did not meet clinical or functional criteria p.Arg75Gln 28 0.00040 48 74 0.01794 0.009-0.033 p.Gly576Alab 42 0.00059 12 20 0.00485 0.004-0.009 p.Arg668Cysc 49 0.00069 16 29 0.00703 0.004-0.009 p.Leu997Phe 28 0.00040 5 9 0.00218 0.001-0.003 p.Arg1162Leu 9 0.00013 2 6 0.00145 0.001 p.Ser1235Arg 54 0.00076 15 21 0.00509 0.005-0.016 aDoes not cause cystic fibrosis unless in cis with the known deleterious variant p.Ile1023_Val1024del66. Login to comment 174 ABCC7 p.Arg668Cys bIn both the 1000 Genomes Project and in this study, this variant is always seen in cis with p.Arg668Cys. Login to comment 175 ABCC7 p.Gly576Ala cIn the 1000 Genomes Project, this variant is always seen in cis with p.Gly576Ala; in this study, it is seen both in cis and on its own. Login to comment 183 ABCC7 p.Gly551Asp ABCC7 p.Phe1052Val ABCC7 p.Gly1069Arg ABCC7 p.Thr360Lys ABCC7 p.Gln359Lys Therefore, we are more confident that more frequent variants such as p.Gly551Asp are fully penetrant than we are for variants such as p.[Gln359Lys; Thr360Lys], p.Phe1052Val and p.Gly1069Arg, which were seen with an allele frequency of less than 0.0002. Login to comment 197 ABCC7 p.Ile1234Val For example, it is possible that one or more of the indeterminate variants cause dysfunction of CFTR in a manner distinct from the functional assessments used in this study, as has been shown for two missense changes that also affect RNA splicing (p.Gly576Ala58 and p.Ile1234Val; A.S.R. and M.D.A., unpublished data). Login to comment 418 ABCC7 p.Gly551Asp Ramsey, B.W. et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. Login to comment 468 ABCC7 p.Ile148Thr Rohlfs, E.M. et al. The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis. Login to comment 509 ABCC7 p.Val1475Met The wild-type CFTR clone was obtained from an individual who did not have cystic fibrosis and encoded the known neutral variant p.Val1475Met. Login to comment