ABCMdb

ABCC7 p.Pro841Arg

ClinVar:	c.2522C>G , p.Pro841Arg ? , not provided
CF databases:	c.2522C>G , p.Pro841Arg (CFTR1) ? , The P841R mutation was detected in the CFTR gene by DGGE and identified by direct sequencing. This mutation has been found in an infertile man with CBAVD carrying the R74W+D1270N mutations on the other allele
Predicted by SNAP2:	A: N (93%), C: N (87%), D: N (93%), E: N (93%), F: N (82%), G: N (93%), H: N (97%), I: N (82%), K: N (93%), L: N (87%), M: N (82%), N: N (97%), Q: N (93%), R: N (93%), S: N (97%), T: N (97%), V: N (87%), W: N (66%), Y: N (87%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Do common in silico tools predict the clinical con... Clin Genet. 2010 May;77(5):464-73. Epub 2009 Jan 6. Dorfman R, Nalpathamkalam T, Taylor C, Gonska T, Keenan K, Yuan XW, Corey M, Tsui LC, Zielenski J, Durie P
Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?
Clin Genet. 2010 May;77(5):464-73. Epub 2009 Jan 6., [PMID:20059485]

Abstract [show]
Computational methods are used to predict the molecular consequences of amino-acid substitutions on the basis of evolutionary conservation or protein structure, but their utility in clinical diagnosis or prediction of disease outcome has not been well validated. We evaluated three popular computer programs, namely, PANTHER, SIFT and PolyPhen, by comparing the predicted clinical outcomes for a group of known CFTR missense mutations against the diagnosis of cystic fibrosis (CF) and clinical manifestations in cohorts of subjects with CF-disease and CFTR-related disorders carrying these mutations. Owing to poor specificity, none of tools reliably distinguished between individual mutations that confer CF disease from mutations found in subjects with a CFTR-related disorder or no disease. Prediction scores for CFTR mutations derived from PANTHER showed a significant overall statistical correlation with the spectrum of disease severity associated with mutations in the CFTR gene. In contrast, PolyPhen- and SIFT-derived scores only showed significant differences between CF-causing and non-CF variants. Current computational methods are not recommended for establishing or excluding a CF diagnosis, notably as a newborn screening strategy or in patients with equivocal test results.

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64 Mutations in the CFTR gene grouped by clinical category Cystic fibrosis CFTR-related disease No disease T338I D614G L320V V920L L90S M470V H199R S1251N I203M G550R P111A I148T Q1291H R560K L1388Q L183I R170H I1027T S549R D443Y P499A L1414S T908N R668C S549N A455E E1401K Q151K G27E I1234L Y563N R347P C866R S1118C P1290S R75Q A559T V520F P841R M469V E1401G P67L G85E S50Y E1409K R933G G458V G178R Y1032C R248T I980K G85V V392G L973P L137H T351S R334W I444S V938G R792G R560T R555G L1339F D1305E P574H V1240G T1053I D58G G551D L1335P I918M F994C S945L L558S F1337V R810G D1152H G1247R P574S R766M D579G W1098R H949R F200I R352Q L1077P K1351E M244K L206W M1101K D1154G L375F N1303K R1066C E528D D110Y R347H R1070Q A800G P1021S S549K A1364V V392A damaging` (is supposed to affect protein function or structure) and 'probably damaging` (high confidence of affecting protein function or structure). Login to comment

[hide] Orphan missense mutations in the cystic fibrosis t... J Mol Diagn. 2011 Sep;13(5):520-7. Epub 2011 Jun 25. Fresquet F, Clement R, Norez C, Sterlin A, Melin P, Becq F, Kitzis A, Thoreau V, Bilan F
Orphan missense mutations in the cystic fibrosis transmembrane conductance regulator a three-step biological approach to establishing a correlation between genotype and phenotype.
J Mol Diagn. 2011 Sep;13(5):520-7. Epub 2011 Jun 25., [PMID:21708286]

Abstract [show]
More than 1860 mutations have been found within the human cystic fibrosis transmembrane conductance regulator (CFTR) gene sequence. These mutations can be classified according to their degree of severity in CF disease. Although the most common mutations are well characterized, few data are available for rare mutations. Thus, genetic counseling is particularly difficult when fetuses or patients with CF present these orphan variations. We describe a three-step in vitro assay that can evaluate rare missense CFTR mutation consequences to establish a correlation between genotype and phenotype. By using a green fluorescent protein-tagged CFTR construct, we expressed mutated proteins in COS-7 cells. CFTR trafficking was visualized by confocal microscopy, and the cellular localization of CFTR was determined using intracellular markers. We studied the CFTR maturation process using Western blot analysis and evaluated CFTR channel activity by automated iodide efflux assays. Of six rare mutations that we studied, five have been isolated in our laboratory. The cellular and functional impact that we observed in each case was compared with the clinical data concerning the patients in whom we encountered these mutations. In conclusion, we propose that performing this type of analysis for orphan CFTR missense mutations can improve CF genetic counseling.

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56 CFTR mutational analysis revealed a complex genotype: p.[Arg74Trp;Val201Met;Asp1270Asn] ϩ [Pro841Arg]. Login to comment
97 Sequences of Site-Directed Mutagenesis Primers Mutation Sense oligonucleotide sequences L102P 5=-GTACAGCCTCTCTTACCGGGAAGAATCATAGCTTCC-3= L167R 5=-AAGAAGACTTTAAAGCGGTCAAGCCGTGTTCTAG-3= P574S 5=-GCTGATTTGTATTTATTAGACTCTTCTTTTGGATACCTAGATG-3= V562I 5=-AGAATTTCTTTAGCAAGAGCAATATACAAAGATGCTGATTTG-3= K696R 5=-CAGACTGGAGAGTTTGGGGAAAGAAGGAAGAATTCTATTCTC-3= P841R 5=-GATATGGAGAGCATACGAGCAGTGACTACATGG-3= CFTR Missense Mutation Biological Assay 3 JMD Month 2011, Vol. xx, No. Login to comment
109 Mixed Phenotype with P574S CFTR Variant The missense substitution p.[Pro574Ser] (P574S) lies within nucleotide-binding domain 1. Login to comment
119 Decreased Activity of K696R and P841R CFTR Mutants Two missense mutations, K696R and p.[Pro841Arg] (P841R), are situated within the cytoplasmic regulator domain of CFTR. Login to comment
122 Summary of the Patients` Data, Concerning Genotype, Phenotype, and Protein Dysfunction Patient no./sex/age at molecular diagnostics (years) Genotype Phenotype Protein dysfunctions Channel activity* Maturation† Intracellular localization‡ 1/F/3 p.[Leu102Pro] ϩ [Arg553X] Positive sweat test result, bacterial lung colonization, no pancreatitis ϩϩ ϩϩ ϩϩ 2/F/newborn p.[Phe508del] ϩ [Leu167Arg] Positive sweat test result, recurrent pancreatitis, no lung infection ϩϩ ϩϩ ϩϩ 3/F/3 p.[Asn1303Lys] ϩ [Pro574Ser] Normal sweat test result, asymptomatic ϩϩ ϩ ϩ 4/M/31 p.[Arg74Trp;Val201Met; Asp1270Asn] ϩ [Pro841Arg]; c. Login to comment
133 After using Western blot analysis (Figure 3B), the proportions of core-glycosylated protein for K696R and P841R appear insignificantly different from that of WT-CFTR (n ϭ 3, data not shown). Login to comment
134 Moreover, we observe by iodide efflux experiments that both mutations have similar functional consequence on CFTR activity: the maximum activation is reduced to 49.67% Ϯ 2.61% (n ϭ 4) for K696R and to 45.10% Ϯ 4.94% (n ϭ 4) for P841R (Figure 3C). Login to comment
161 B A calreticulin egremS475P calreticulin egremS475P WT F508del P574S CFTR C WT F508del P574S CFTR C B CFTR NaKATPase B CFTR NaKATPase C WT P574S *** WT P574S ***** 00 WT P574S 0 00 00 00 00 **** 00 WT P574S 0 00 00 00 00 0 50 100 WT % of maximal activation 0 50 100 WT % of maximal activationB/(B+C) (%) 100 0 200 300 400 500 B/(B+C) (%) 100 0 200 300 400 500 Figure 2. Login to comment
162 P574S amino acid substitution decreases CFTR protein maturation. Login to comment
192 One possible explanation could be that iodide effluxes are not sensitive enough to precisely evaluate the CFTR chloride channel activation process; notably, CFTR channel open probability could not be studied directly by this A B C P841R actin merge +TO-PRO K696R actin merge +TO-PRO P841R actin merge +TO-PRO K696R actin merge +TO-PRO % of maximal activation ** ** 0 50 100 WT K696R P841R % of maximal activation ** ** 0 50 100 WT K696R P841R % of maximal activation ** ** 0 50 100 WT K696R P841R WT F508del P841R K696R B CFTR NaKATPase C WT F508del P841R K696R B CFTR NaKATPase C Figure 3. Login to comment
193 K696R and P841R amino acid substitutions affect CFTR channel activity. Login to comment
209 Our results suggest a mild phenotype for the K696R and P841R CFTR mutants: the trafficking and maturation rates appear normal, whereas activation is approximately half reduced. Login to comment
211 The variant K696R was isolated from a familial study, in which we did not find any other CFTR mutation. Login to comment
213 The P841R variant was carried by a patient with CBAVD, referred for pre-ICSI assessment; his spouse was heterozygous compound for p.[Phe508del]. Login to comment
214 His genotype was p.[Pro841Arg] ϩ [Arg74Trp;Val201Met; Asp1270Asn]. Login to comment
215 The complex CFTR allele harboring three substitutions is considered responsible for a mild phenotype because a case of homozygosis has been reported for a patient exhibiting CBAVD, without severe CF features.22 Because the genotype of the patient results in CBAVD, we can deduce that P841R is either a mild or a severe mutation. Login to comment
216 Therefore, in the case of ICSI, it was decided by a pluridisciplinary antenatal staff that, if the resulting fetuses carried P841R and F508del alleles, this couple would be offered a therapeutic abortion, given the high risk of CF for the evaluated offspring.18 Our biological data are not fully in accordance with this conclusion because the P841R variant seems to not cause a severe CF phenotype because the CFTR protein could reach the plasma membrane and could be activated. Login to comment
217 Taken together, these data strongly suggest that P841R is more likely to be a mild than a severe CF mutation. Login to comment
60 Sequences of Site-Directed Mutagenesis Primers Mutation Sense oligonucleotide sequences L102P 5=-GTACAGCCTCTCTTACCGGGAAGAATCATAGCTTCC-3= L167R 5=-AAGAAGACTTTAAAGCGGTCAAGCCGTGTTCTAG-3= P574S 5=-GCTGATTTGTATTTATTAGACTCTTCTTTTGGATACCTAGATG-3= V562I 5=-AGAATTTCTTTAGCAAGAGCAATATACAAAGATGCTGATTTG-3= K696R 5=-CAGACTGGAGAGTTTGGGGAAAGAAGGAAGAATTCTATTCTC-3= P841R 5=-GATATGGAGAGCATACGAGCAGTGACTACATGG-3= was presented. Login to comment
81 Summary of the Patients` Data, Concerning Genotype, Phenotype, and Protein Dysfunction Patient no./sex/age at molecular diagnostics (years) Genotype Phenotype Protein dysfunctions Channel activity* Maturation† Intracellular localization‡ 1/F/3 p.[Leu102Pro] ϩ [Arg553X] Positive sweat test result, bacterial lung colonization, no pancreatitis ϩϩ ϩϩ ϩϩ 2/F/newborn p.[Phe508del] ϩ [Leu167Arg] Positive sweat test result, recurrent pancreatitis, no lung infection ϩϩ ϩϩ ϩϩ 3/F/3 p.[Asn1303Lys] ϩ [Pro574Ser] Normal sweat test result, asymptomatic ϩϩ ϩ ϩ 4/M/31 p.[Arg74Trp;Val201Met; Asp1270Asn] ϩ [Pro841Arg]; c. Login to comment
110 K696R and P841R amino acid substitutions affect CFTR channel activity. Login to comment
158 Decreased Activity of K696R and P841R CFTR Mutants Two missense mutations, p.Lys696Arg (K696R) and p.Pro841Arg (P841R), are situated within the cytoplasmic regulator domain of CFTR. Login to comment
205 Our results suggest a mild phenotype for the K696R and P841R CFTR mutants: the trafficking and maturation rates appear normal, whereas activation is approximately half reduced. Login to comment
210 His genotype was p.[Pro841Arg] ϩ [Arg74Trp;Val201Met; Asp1270Asn]. Login to comment
212 Therefore, in the case of ICSI, it was decided by a pluridisciplinary antenatal staff that, if the resulting fetuses carried P841R and F508del alleles, this couple would be offered a therapeutic abortion, given the high risk of CF for the evaluated offspring.18 Our biological data are not fully in accordance with this conclusion because the P841R variant seems to not cause a severe CF phenotype because the CFTR protein could reach the plasma membrane and could be activated. Login to comment

[hide] Outcome of intracytoplasmic sperm injection for a ... Fertil Steril. 2008 Nov;90(5):2004.e23-6. Epub 2008 Aug 13. Brugnon F, Bilan F, Heraud MC, Grizard G, Janny L, Creveaux I
Outcome of intracytoplasmic sperm injection for a couple in which the man is carrier of CFTR p.[R74W;V201M;D1270N] and p.P841R mutations and his spouse a heterozygous carrier of p.F508del mutation of the cystic fibrosis transmembrane conductance regulator gene.
Fertil Steril. 2008 Nov;90(5):2004.e23-6. Epub 2008 Aug 13., [PMID:18703181]

Abstract [show]
OBJECTIVE: To document the phenotype associated with the p.[R74W;V201M;D1270N] and p.P841R mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene. DESIGN: Case report. SETTING: Biology and medicine of reproduction in a university hospital. PATIENT(S): A couple in which the man is carrier of the triple mutant p.[R74W;V201M;D1270N] allele in trans to p.P841R mutation and his spouse a heterozygous carrier for the severe p.F508del mutation of the CFTR gene, who became pregnant after intracytoplasmic sperm injection (ICSI) with twins. INTERVENTION(S): Genetic counseling; CFTR gene sequencing; ICSI; children's follow-up. MAIN OUTCOME MEASURE(S): First report of a male phenotype associated with the p.P841R mutation. RESULT(S): The triple mutant p.[R74W;V201M;D1270N] allele associated with the unknown p.P841R mutations were detected in this man with congenital bilateral absence of the vas deferens, which may presume p.P841R as a severe mutation. After genetic counseling, the couple preferred prenatal diagnosis after ICSI than preimplantation genetic diagnosis, which revealed that the boys were both carriers of p.[R74W;V201M;D1270N] and p.F508del mutations. They are now 4 years old and show normal growth without nutritional deficiency. CONCLUSION(S): This case report documents for the first time a male phenotype associated with the p.P841R mutation and underlines the difficulties in counseling a man with congenital bilateral absence of the vas deferens carrying uncommon mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene before ICSI.

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0 CASE REPORT Outcome of intracytoplasmic sperm injection for a couple in which the man is carrier of CFTR p.[R74W;V201M;D1270N] and p.P841R mutations and his spouse a heterozygous carrier of p.F508del mutation of the cystic fibrosis transmembrane conductance regulator gene Florence Brugnon, M.D.,a Frederic Bilan, Ph.D.,b Marie-Christine Heraud, M.D.,c Genevieve Grizard, Ph.D.,a Laurent Janny, M.D.,a and Isabelle Creveaux, M.D., Ph.Dd a CHU Clermont-Ferrand, Biologie du Developpement et de la Reproduction, CECOS, H^otel Dieu, Clermont Ferrand; b CHU Poitiers, Laboratoire de Genetique Cellulaire et Moleculaire, Universite de Poitiers, UFR Medecine-Pharmacie, Poitiers; c CHU Clermont Ferrand, Pediatrie A, H^otel Dieu; and d CHU Clermont Ferrand, Laboratoire de biochimie medicale et biologie moleculaire, Faculte de Medecine, Clermont Ferrand, France Objective: To document the phenotype associated with the p.[R74W;V201M;D1270N] and p.P841R mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene. Login to comment
3 Patient(s): A couple in which the man is carrier of the triple mutant p.[R74W;V201M;D1270N] allele in trans to p.P841R mutation and his spouse a heterozygous carrier for the severe p.F508del mutation of the CFTR gene, who became pregnant after intracytoplasmic sperm injection (ICSI) with twins. Login to comment
5 Main Outcome Measure(s): First report of a male phenotype associated with the p.P841R mutation. Login to comment
6 Result(s): The triple mutant p.[R74W;V201M;D1270N] allele associated with the unknown p.P841R mutations were detected in this man with congenital bilateral absence of the vas deferens, which may presume p.P841R as a severe mutation. Login to comment
9 Conclusion(s): This case report documents for the first time a male phenotype associated with the p.P841R mutation and underlines the difficulties in counseling a man with congenital bilateral absence of the vas deferens carrying uncommon mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene before ICSI. Login to comment
12 Key Words: CFTR, [p.R74W;p.V201M;p.1270N], p.P841R, genetic counseling, ICSI, CBAVD Treatment by assisted reproductive technology (ART) of infertile men with congenital bilateral absence of the vas deferens (CBAVD) associated with mutations of the CFTR gene changed after the introduction of intracytoplasmic sperm injection (ICSI) with epididymal or testicular spermatozoa (1). Login to comment
16 The purpose of this case report is to describe and analyze the outcome of an infertile couple in which the man with CBAVD is carrier of rare mutations of the CFTR gene p.[R74W;V201M;D1270N] þ p.P841R and his spouse, a heterozygous carrier for F508del. Login to comment
17 To our knowledge, this is the first report that describes the phenotype of an infertile man with CBAVD carrying p.P841R. Login to comment
40 Results revealed that the man was a compound heterozygous carrier of the triple mutant p.[R74W;V201M;D1270N] allele and the unknown p.P841R mutation (Fig. Login to comment
42 Segregation analysis of the man`s parents revealed that his father transmitted the CFTR p.P841R mutation and his mother, the complex allele p.[R74W;V201M;D1270N]. Login to comment
43 To our knowledge the significance of CFTR p.P841R has never been described to date, and its functional significance is unknown. Login to comment
54 (a) p.D1270N mutation (3940 G>A); (b) p.R74W mutation (352 C>T); (c) p.P841R mutation (2854 C>G). Login to comment
65 Nevertheless, it is extremely difficult to predict the risks of inheritance of uncommon or newly identified mutations whose phenotype has never been described, such as the p.P841R mutation. Login to comment
66 The p.P841R mutation leads to the substitution of a proline for an arginine in exon 14a. Login to comment
82 The CBAVD phenotype described in homozygous p.[R74W;V201M;D1270N] patients (3) suggests that we can consider this triple mutant allele as mild. Login to comment
84 During genetic counseling before ICSI, the couple was given explanations concerning the high risk of CF for the children if both p.F508del and p.P841R were inherited, respectively, from their mother and father, and the risk of CBAVD if p.[R74W;V201M;D1270N] and p.F508del were inherited. Login to comment
88 If the fetus were found to be a carrier of p.P841R and p.F508del, the couple was offered therapeutic abortion, given the high risk of CF for the offspring. Login to comment
39 Results revealed that the man was a compound heterozygous carrier of the triple mutant p.[R74W;V201M;D1270N] allele and the unknown p.P841R mutation (Fig. 1) and his spouse was a heterozygous carrier for p.F508del. Login to comment
41 To our knowledge the significance of CFTR p.P841R has never been described to date, and its functional significance is unknown. Login to comment
52 (a) p.D1270N mutation (3940 G>A); (b) p.R74W mutation (352 C>T); (c) p.P841R mutation (2854 C>G). Login to comment
63 Nevertheless, it is extremely difficult to predict the risks of inheritance of uncommon or newly identified mutations whose phenotype has never been described, such as the p.P841R mutation. Login to comment
64 The p.P841R mutation leads to the substitution of a proline for an arginine in exon 14a. Login to comment
86 If the fetus were found to be a carrier of p.P841R and p.F508del, the couple was offered therapeutic abortion, given the high risk of CF for the offspring. Login to comment