ABCMdb

PMID: 26014425

Girardet A, Viart V, Plaza S, Daina G, De Rycke M, Des Georges M, Fiorentino F, Harton G, Ishmukhametova A, Navarro J, Raynal C, Renwick P, Saguet F, Schwarz M, SenGupta S, Tzetis M, Roux AF, Claustres M
The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus.
Eur J Hum Genet. 2015 May 27. doi: 10.1038/ejhg.2015.99., [PubMed]

Sentences

No. Mutations Sentence Comment

35 ABCC7 p.Arg117His ABCC7 p.Arg117His In CBAVD men from European descent, the two most common genotypes are p.Phe508del in trans either with the '5T allele` in intron 8 (now designated as c.1210-12T[5] in intron 9) (30%) or with the variants R117H-7T (p. Arg117His associated with a 7T allele (c.1210-12T[7]) (6%). Login to comment 76 ABCC7 p.Phe508Cys ABCC7 p.Ile507Val For example, inability to confirm the variants in both parents may be found in cases with apparent homozygosity for a common or a rare variant: Nonpaternity Presence on the opposite allele of a large deletion, nonrevealed by routine tests Presence of a rare SNP in primer-binding sites or a rare DNA variant that causes failure of amplification and/or hybridization of a probe: for example, false homozygosity for p.Phe508del due to the presence of the variant F508C (c.1523T4G); false homozygosity for p.Ile507del due to the presence of p.Ile507Val (I597V) (c.1519A4G). Login to comment 78 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Gln493* ABCC7 p.Arg560Thr ABCC7 p.Arg560Thr ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys Table 1 Examples of common CF-causing, indetermined, and non CF-causing variants (modified from5,8,17) HGVS nomenclature Legacy name cDNA nucleotide name Protein name CF-causing variantsa F508del c.1521_1523delCTT p.Phe508del G542X c.1624G4T p.Gly542* G551D c.1652G4A p.Gly551Asp N1303K c.3909C4G p.Asn1303Lys W1282X c.3846G4A p.Trp1282* 621+1G4T c.489+1G4T CFTRdele2,3 c.54-5940_273 +10250del21080 p.Ser18Argfs*16 E60X c.178G4T p.Glu60* G85E c.254G4A p.Gly85Glu 394delTT c.262_263delTT p.Leu88Ilefs*22 711+1G4T c.579+1G4T R347P c.1040G4C p.Arg347Pro A455E c.1364C4A p.Ala455Glu Q493X c.1477C4T p.Gln493* I507del c.1519_1521delATC p.Ile507del R553X c.1657C4T p.Arg553* R560T c.1679G4C p.Arg560Thr 1898+1G4A c.1766+1G4A 2183AA4G c.2051_2052delAAinsG p.Lys684Serfs*38 2789+5G4A c.2657+5G4A 3120+1G4A c.2988+1G4A M1101K c.3302 T4A p.Met1101Lys R1162X c.3484C4T p.Arg1162* 3659delC c.3528delC p.Lys1177Serfs*15 M1V c.1 A4G p.? Login to comment 79 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Glu831* ABCC7 p.Pro205Ser ABCC7 p.Pro205Ser ABCC7 p.Glu585* ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn ABCC7 p.Ser549Asn ABCC7 p.Tyr122* ABCC7 p.Pro67Leu ABCC7 p.Pro67Leu ABCC7 p.Thr338Ile ABCC7 p.Thr338Ile ABCC7 p.Gln220* ABCC7 p.His199Tyr ABCC7 p.His199Tyr ABCC7 p.Ser945Leu ABCC7 p.Ser945Leu ABCC7 p.Gln39* ABCC7 p.Gln552* ABCC7 p.Lys710* ABCC7 p.Gly970Arg ABCC7 p.Gly970Arg ABCC7 p.Gln98* ABCC7 p.Arg764* ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys ABCC7 p.Ser489* ABCC7 p.Gln890* ABCC7 p.Arg75* ABCC7 p.Glu92Lys ABCC7 p.Glu92Lys ABCC7 p.Trp846* ABCC7 p.Trp846* ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys ABCC7 p.Arg851* ABCC7 p.Arg560Lys ABCC7 p.Arg560Lys ABCC7 p.Ser492Phe ABCC7 p.Ser492Phe ABCC7 p.Asp110His ABCC7 p.Asp110His ABCC7 p.Gly330* ABCC7 p.Ala559Thr ABCC7 p.Ala559Thr ABCC7 p.Arg709* ABCC7 p.Glu822* ABCC7 p.Glu92* ABCC7 p.Ser466* ABCC7 p.Leu927Pro ABCC7 p.Leu927Pro ABCC7 p.Leu732* ABCC7 p.Leu467Pro ABCC7 p.Leu467Pro ABCC7 p.Ser341Pro ABCC7 p.Ser341Pro (unknown) Q39X c.115C4T p.Gln39* P67L c.200C4T p.Pro67Leu R75X c.223C4T p.Arg75* 405+1G4A c.273+1G4A 406-1G4A c.274-1G4A E92X c.274G4T p.Glu92* E92K c.274G4A p.Glu92Lys Q98X c.292C4T p.Gln98* 457TAT4G c.325_327delTATinsG p.Tyr109Glyfs*4 D110H c.328G4C p.Asp110His R117C c.349C4T p.Arg117Cys Y122X c.366 T4A p.Tyr122* 574delA c.442delA p.Ile148Leufs*5 444delA c.313delA p.Ile105Serfs*2 663delT c.531delT p.Ile177Metfs*12 G178R c.532G4A p.Gly178Arg 711+3 A4G c.579+3 A4G 711+5G4A c.579+5G4A 712-1G4T c.580-1G4T H199Y c.595C4T p.His199Tyr P205S c.613C4T p.Pro205Ser L206W c.617 T4G p.Leu206Trp Q220X c.658C4T p.Gln220* 852del22 c.720_741delAGGGAGAAT GATGATGAAGTAC p.Gly241Glufs*13 1078delT c.948delT p.Phe316Leufs*12 G330X c.988G4T p.Gly330* Table 1 (Continued ) HGVS nomenclature Legacy name cDNA nucleotide name Protein name R334W c.1000C4T p.Arg334Trp I336K c.1007 T4A p.Ile336Lys T338I c.1013C4T p.Thr338Ile 1154insTC c.1021_1022dupTC p.Phe342Hisfs*28 S341P c.1021 T4C p.Ser341Pro R347H c.1040G4A p.Arg347His 1213delT c.1081delT p.Trp361Glyfs*8 1248+1G4A c.1116+1G4A 1259insA c.1130dupA p.Gln378Alafs*4 W401X(TAG) c.1202G4A p.Trp401* W401X(TGA) c.1203G4A p.Trp401* 1341+1G4A c.1209+1G4A 1461ins4 c.1329_1330insAGAT p.Ile444Argfs*3 1525-1G4A c.1393-1G4A S466X c.1397C4A or c.1397C4G p.Ser466* L467P c.1400 T4C p.Leu467Pro S489X c.1466C4A p.Ser489* S492F c.1475C4T p.Ser492Phe 1677delTA c.1545_1546delTA p.Tyr515* V520F c.1558G4T p.Val520Phe 1717-1G4A c.1585-1G4A 1717-8G4A c.1585-8G4A S549R c.1645 A4C p.Ser549Arg S549N c.1646G4A p.Ser549Asn S549R c.1647 T4G p.Ser549Arg Q552X c.1654C4T p.Gln552* A559T c.1675G4A p.Ala559Thr 1811+1.6kbA4G c.1680-886 A4G 1812-1G4A c.1680-1G4A R560K c.1679G4A p.Arg560Lys E585X c.1753G4T p.Glu585* 1898+3 A4G c.1766+3 A4G 2143delT c.2012delT p.Leu671* 2184insA c.2052_2053insA p.Gln685Thrfs*4 2184delA c.2052delA p.Lys684Asnfs*38 R709X c.2125C4T p.Arg709* K710X c.2128 A4T p.Lys710* 2307insA c.2175dupA p.Glu726Argfs*4 L732X c.2195 T4G p.Leu732* 2347delG c.2215delG p.Val739Tyrfs*16 R764X c.2290C4T p.Arg764* 2585delT c.2453delT p.Leu818Trpfs*3 E822X c.2464G4T p.Glu822* 2622+1G4A c.2490+1G4A E831X c.2491G4T p.Glu831* W846X c.2537G4A p.Trp846* W846X (2670TGG4TGA) c.2538G4A p.Trp846* R851X c.2551C4T p.Arg851* 2711delT c.2583delT p.Phe861Leufs*3 S945L c.2834C4T p.Ser945Leu 2789+2insA c.2657+2_2657+3insA Q890X c.2668C4T p.Gln890* L927P c.2780 T4C p.Leu927Pro 3007delG c.2875delG p.Ala959Hisfs*9 G970R c.2908G4C p.Gly970Arg 3120G4A c.2988G4A function variants that cause CF disease when paired together; (ii) variants that retain residual CFTR function and are compatible with milder phenotypes such as CFTR-RD; (iii) variants with no clinical consequences; and (iv) variants of unproven or uncertain clinical relevance. Login to comment 83 ABCC7 p.Leu1065Pro ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Trp1089* ABCC7 p.Leu1077Pro ABCC7 p.Leu1077Pro ABCC7 p.Ser1196* ABCC7 p.Arg1066His ABCC7 p.Arg1066His ABCC7 p.Glu1104* In several countries, when at least one Table 1 (Continued ) HGVS nomenclature Legacy name cDNA nucleotide name Protein name 3121-1G4A c.2989-1G4A 3199del6 (3195del6) c.3067_3072delATAGTG p.Ile1023_Val1024del 3272-26 A4G c.3140-26 A4G L1065P c.3194 T4C p.Leu1065Pro R1066C c.3196C4T p.Arg1066Cys R1066H c.3197G4A p.Arg1066His L1077P c.3230 T4C p.Leu1077Pro W1089X c.3266G4A p.Trp1089* Y1092X c.3276C4A p.Tyr1092* E1104X c.3310G4T p.Glu1104* R1158X c.3472C4T p.Arg1158* S1196X c.3587C4G p.Ser1196* W1204X(3743G4A) c.3611G4A p.Trp1204* W1204X(3744G4A) c.3612G4A p.Trp1204* 3791delC c.3659delC p.Thr1220Lysfs*8 3849+10kbC4T c.3718-2477C4T p.(?) Login to comment 84 ABCC7 p.Gly1244Glu ABCC7 p.Gly1244Glu ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Gln1313* G1244E c.3731G4A p.Gly1244Glu 3876delA c.3744delA p.Lys1250Argfs*9 S1251N c.3752G4A p.Ser1251Asn 3905insT c.3773dupT p.Leu1258Phefs*7 4005+1G4A c.3873+1G4A 4016insT c.3889dupT p.Ser1297Phefs*5 Q1313X c.3937C4T p.Gln1313* CFTRdele22,23 c.3964-78_4242+577del p. Login to comment 85 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Thr360Lys ABCC7 p.Gln359Lys ABCC7 p.Leu227Arg ABCC7 p.Leu227Arg (Gly1323_Val1415del) 4209TGTT4AA c.4077_4080delTGTTinsAA 4382delA c.4251delA p.Glu1418Argfs*14 Examples of common variants with varying or indetermined clinical consequencesb R117H c.350G4A p.Arg117His L227R c.680 T4G p.Leu227Arg Q359K/T360K c. Login to comment 87 ABCC7 p.Val754Met ABCC7 p.Val754Met ABCC7 p.Asp1270Asn ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg74Trp ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Gln ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Tyr569Asp ABCC7 p.Tyr569Asp ABCC7 p.Phe1052Val ABCC7 p.Phe1052Val ABCC7 p.Arg668Cys ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Gly576Ala ABCC7 p.Arg31Cys ABCC7 p.Arg31Cys ABCC7 p.Ile1234Val ABCC7 p.Ile1234Val ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr ABCC7 p.Arg1162Leu ABCC7 p.Arg1162Leu ABCC7 p.Leu558Ser ABCC7 p.Leu558Ser ABCC7 p.Arg1070Trp ABCC7 p.Arg1070Trp ABCC7 p.Gly1069Arg ABCC7 p.Gly1069Arg ABCC7 p.Thr360Lys ABCC7 p.Ser977Phe ABCC7 p.Ser977Phe ABCC7 p.Gln359Lys ABCC7 p.Asp614Gly ABCC7 p.Asp614Gly ABCC7 p.Asp579Gly ABCC7 p.Asp579Gly [Gln359Lys; Thr360Lys] L558S c.1673 T4C p.Leu558Ser Y569D c.1705 T4G p.Tyr569Asp D579G c.1736 A4G p.Asp579Gly D614G c.1841 A4G p.Asp614Gly S977F c.2930C4T p.Ser977Phe F1052V c.3154 T4G p.Phe1052Val G1069R c.3205G4A p.Gly1069Arg R1070Q c.3209G4A p.Arg1070Gln D1152H c.3454G4C p.Asp1152His I1234V c.3700 A4G p.Ile1234Val 5T c.1210 - 12[5] Examples of common not CF-causing variantsc R31C c.91C4T p.Arg31Cys R74W c.220C4T p.Arg74Trp R75Q c.224G4A p.Arg75Gln I148T c.443 T4C p.Ile148Thr M470V c.1408 A4G p.Met470Val G576A c.1727G4C p.Gly576Ala R668C c.2002C4T p.Arg668Cys V754M c.2260G4A p.Val754Met L997F c.2991G4C p.Leu997Phe I1027T c.3080 T4C p.Ile1027Thr R1070W c.3208C4T p.Arg1070Trp R1162L c.3485G4T p.Arg1162Leu Table 1 (Continued) HGVS nomenclature Legacy name cDNA nucleotide name Protein name S1235R c.3705 T4G p.Ser1235Arg D1270N c.3808G4A p.Asp1270Asn 7T c.1210-12[7] Abbreviation: HGVS, Human Genome Variation Society. Login to comment 92 ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Leu206Trp ABCC7 p.Arg117Cys ABCC7 p.Arg1066His ABCC7 p.Asp110His Well known examples include missense variants D110H, R117C, L206W, R347P, R347H, R1066H, or splice variants that produce both aberrant and full-length transcript such as 3849+10kbC4T, 2789+5G4A, 3272-26 A4G, 711+3 A4G. Login to comment 96 ABCC7 p.Arg117His The most studied examples are R117H and the 5 T allele. Login to comment 97 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His When paired in trans with a severe CF variant, R117H is considered as causing CFTR-RD (or rarely mild CF-PS) if associated in cis with a 5 T allele (rare occurence), whereas it is considered as a neutral or CFTR-RD variant when associated in cis with the common 7 T allele.11 Owing to the extremely low penetrance of R117H for CF,18 in some countries this variant has been removed from the newborn CF screening panels, as its presence created both management and counseling dilemmas (many healthy carriers of R117H-7 T could be wrongly considered as CF carriers and prenatal diagnosis inappropriately proposed). Login to comment 99 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg1070Trp Missense variants R74W, R1070W, D1270N are classified as 'indeterminate` by Sosnay et al.,17 however, as they are frequently found in trans with a severe CF variant in asymptomatic individuals (including fertile fathers), they may not be sufficient to cause disease.19 Moreover, they are often associated within the same allele (eg in cis), forming various combinations ('complex alleles`) depending on individuals, so that their disease liability is questionable. Login to comment 100 ABCC7 p.Arg74Trp Examples: [R74W;D1270N] c. Login to comment 101 ABCC7 p.Arg74Trp [220C4T;3808G4A] [R74W;V201M;D1270N] c. Login to comment 102 ABCC7 p.Arg74Trp [220C4T;601G4A;3808G4A] [R74W;R1070W;D1270N] c. Login to comment 103 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Arg668Cys ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Gly576Ala [220C4T;c.3208C4T;3808G4A] I148T is a neutral variant, but can be associated in cis with a severe CF variant c.3067_3072del (legacy 3199del6 or 3195del6) that, in isolation causes CF, whereas I148T in isolation does not.19,20 G576A is found in cis with R668C and R668C can be found alone or in cis with G576A. Login to comment 104 ABCC7 p.Arg117His ABCC7 p.Asp1270Asn ABCC7 p.Arg75Gln ABCC7 p.Ser1235Arg ABCC7 p.Asp1152His ABCC7 p.Leu997Phe ABCC7 p.Ile1027Thr ABCC7 p.Arg170His ABCC7 p.Leu967Ser ABCC7 p.Arg74Gln I1027T is usually found in cis with F508del: Notes: (i) Some missense variants classified as either indeterminate or non CF-causing (R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R and D1270N) can selectively alter the bicarbonate permeation of the CFTR channel (but not the chloride channel), thus affecting primarily the organs that utilize CFTR for bicarbonate secretion (pancreas, nasal sinus, or vas deferens) and, consequently, they could be involved in the pathogenic mechanisms of CFTR-RDs.14 (ii) In Table 1, the traditional name of common CFTR variants is referenced alongside the HGVS version in order to ensure compatibility with clinical reports and understanding by clinicians and couples. Login to comment 113 ABCC7 p.Gly551Asp [1521_1523delCTT];[489+1G4T] Two variants, phase unknown example 1b F508del and G551D c. Login to comment 114 ABCC7 p.Asn1303Lys [1521_1523delCTT(;)1652G4A] Two variants, phase unknown example 2b 3849+10kbC4T and N1303K c. Login to comment 115 ABCC7 p.Arg117His [3718-2477C4T(;)3909C4G] Two heterozygote variants on one allele (in cis) R117H-T5/normal c. Login to comment 126 ABCC7 p.Arg117His ABCC7 p.Leu206Trp ABCC7 p.Arg1162Leu ABCC7 p.Pro1013His Prenatal diagnosis, Preimplantation genetic diagnosis, offered to Parents of a CF patient Carrier couples identified through carrier testing Carrier couples identified through investigations for fetal bowel anomalies Couples with one individual affected with CF and a carrier partner Couples with one individual affected with CBAVD and a carrier partner Table 4 Inclusion and exclusion criteria for CF-PGD according to countries France Italy Spain Belgium Greece UK USA Parents 1 affected+1 carrier S/LS A A A A A A A 1 affected+1 carrier M R A A A A A A 1 affected+1 carrier U A A A A R Aਭ A 2 carriers S/LS A A A A A A A 1 carrier S/LS+1 carrier M R A A A A A A 1 carrier S/LS+1 carrier U A A A A R Aਭ A Abbreviations: S, severe CF-causing variant (p.Phe508del, p.Gly542ਭߪ); LS, large spectrum variant (p.Leu206Trp, c.2657+5G4A ߪ); M, mild variant with variable disease penetrance (IVS8-5 T allele, p.Arg117His-7 T ߪ); U, variants of unproven or uncertain CF clinical relevance (p.Pro1013His, p.Arg1162Leu ߪ); A, accepted; R, refused. Login to comment 211 ABCC7 p.Arg117His ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp Nat Genet 2013; 45: 1160-1167. 18 Thauvin-Robinet C, Munck A, Huet F et al: The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. J Med Genet 2009; 46: 752-758. 19 Claustres M, Altieri JP, Guittard C, Templin C, Chevalier-Ports F, Des Georges M: Are p.148 T, p.R74W and p.D1270N CF causing mutations? Login to comment 212 ABCC7 p.Ile148Thr BMC Med Genet 2004; 5: 19. 20 Monaghan KG, Highsmith WE, Amos J et al: Genotype-phenotype correlation and frequency of the 3199del6 cystic fibrosis mutation among I148T carriers: results from a collaborative study. Login to comment 234 ABCC7 p.Leu997Phe Hum Mutat 2011; 32: 1197-1203. 42 Strom CM, Redman JB, Peng M: The dangers of including nonclassical cystic fibrosis variants in population-based screening panels: p.L997F, further genotype/phenotype correlation data. Login to comment