ABCMdb

ABCC7 p.Arg933Thr

ClinVar:	c.2797A>G , p.Arg933Gly ? , not provided c.2799A>T , p.Arg933Ser ? , not provided
CF databases:	c.2799A>T , p.Arg933Ser (CFTR1) D , R933S was found in a German patient with CBAVD who is also heterozygous for [delta]F508. c.2797A>G , p.Arg933Gly (CFTR1) D ,
Predicted by SNAP2:	A: D (75%), C: D (66%), D: D (91%), E: D (85%), F: D (75%), G: D (85%), H: D (80%), I: D (75%), K: D (75%), L: D (80%), M: D (71%), N: D (85%), P: D (91%), Q: D (75%), S: D (71%), T: D (71%), V: D (80%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: N, F: D, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: D, Q: N, S: N, T: N, V: N, W: N, Y: N,

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Publications
[hide] Heterogeneous spectrum of mutations in CFTR gene f... Mol Hum Reprod. 2014 Sep;20(9):827-35. doi: 10.1093/molehr/gau047. Epub 2014 Jun 23. Sharma H, Mavuduru RS, Singh SK, Prasad R
Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers.
Mol Hum Reprod. 2014 Sep;20(9):827-35. doi: 10.1093/molehr/gau047. Epub 2014 Jun 23., [PMID:24958810]

Abstract [show]
Cystic fibrosis (CF) is usually considered a rare disease in the Indian population. Two studies have reported on the frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Indian males with congenital absence of the vas deferens (CAVD), however, data on the spectrum of CFTR gene mutations are still lacking. Therefore, the present study was designed to identify the spectrum of CFTR gene mutations as well as to investigate an association of CF genetic modifiers in the penetrance of CAVD in infertile Indian men. A total of 60 consecutive infertile males with a diagnosis of CAVD were subjected to CFTR gene analysis which revealed 13 different CFTR gene mutations and 1 intronic variant that led to aberrant splicing. p.Phe508del (n = 16) and p.Arg117His (n = 4) were among the most common severe forms of CFTR mutations identified. The IVS8-T5 allele, which is considered as a mild form of CFTR mutation, was found with an allelic frequency of 28.3%. Eight novel mutations were also identified in the CFTR gene from our patient cohort. It is noteworthy that the spectrum of CFTR gene mutation is heterogeneous, with exon 4 and exon 11 as hot spot regions. Moreover, we also found an association of the CF genetic modifiers, viz., transforming growth factor (TGF)-beta1 and endothelial receptor type-A (EDNRA) genes with the CAVD phenotype. The findings are of considerable clinical significance because men suffering from infertility due to CAVD can decide to use artificial reproduction technology. The children of men with CAVD are at risk of carrying CFTR mutations; therefore, genetic counseling is a crucial step for such patients. With special reference to developing countries, such as India, where whole gene sequencing is not feasible, the outcome of our study will make the screening procedure for CFTR gene simpler and more cost-effective as we have identified hot spot regions of the CFTR gene which are more prone to mutation in Indian males with CAVD. Moreover, this is the first study from the Indian population to investigate the association of CF genetic modifiers with penetrance of the CAVD phenotype. The observed association of the genetic modifiers TGF-beta1 and EDNRA in the penetrance of CAVD further supports their involvement in genesis of the vas deferens.

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No. Sentence Comment
82 SSCP analysis and subsequent DNA sequencing further revealed eleven mutations, viz., p.Gly480Ser, p.Ser549Asn, p.Arg518Lys, p.Gly126Cys, p.Ala141Gly, p.His139Gln, p.Ser118Pro, p.Arg170Cys, p.Glu585Gln, p.Met281Arg, p.Arg933Thr and two intronic variants c.1679+24G.T, c.1766+48G.C. Login to comment
86 edu/pph2/)for p.Gly126Cys,p.Ser118Pro,p.Met281Arg,p.Arg933Thr were more than 0.5 (threshold for pathological mutation) and therefore categorized as deleterious mutations and may possibly affect CFTR structure and function (Table IV). Login to comment
90 p.Ser118Pro, p.Met281Arg and p.Arg933Thr as pathological damaging CFTR mutations, whereas five other novel mutations were predicted as being neutral by this program (Supplementary data, Table SIII). Login to comment
94 Genotype Number of CAVD subjects (n 5 60) Number of healthy controls (n 5 50) p.Phe508del/U 11 ND p.Phe508del/5T 5 ND 5T/5T 8 ND 5T/U 9 7 p.Arg117His/7T 2 ND p.Arg117His/5T 2 ND p.Arg933Thr/U 1 ND p.His139Gln/U 1 ND p.Ser118Pro/c. Login to comment
100 Mutations Nucleotide change Consequences Exon/Intron Number of alleles T5 Reduction of oligo T tract to 5T, c.1210-12T[5] Aberrant splicing Intron 8 34 p.Phe508del c.1521_1523delCTT or c.1522_1524delTTT Deletion of phenylalanine at amino acid 508 Exon 11 16 p.Gly480Ser c.1438G.A Glycine to Serine at 480 Exon 11 1 p.Arg518Lysa c.1553G.A Arginine to Lysine at 518 Exon 11 1 p.Arg117His c.350G.A Arginine to Histidine at 117 Exon 4 4 p.Gly126Cysa c.376G.T Glycine to Cystine at 126 Exon 4 1 p.Ala141Glya c.422C.G Alanine to Glycine at 141 Exon 4 1 p.His139Glna c.417C.G Histadine to Glutamine at 139 Exon 4 1 p.Ser118Proa c.352T.C Serine to Proline at 118 Exon 4 1 p.Arg170Cys c.508C.T Arginine to Cystine at 170 Exon 5 1 p.Glu585Glna c.1753G.C Glutamate to Glutamine at 585 Exon 13 1 p.Met281Arga c.842T.G Methionine to Arginine at 281 Exon 7 1 p.Arg933Thra c.2798G.C Arginine to Threonine at 933 Exon 17 1 p.Ser549Asn c.1646G.A Serine to Asparagine at 549 Exon 12 1 CTFR, cystic fibrosis transmembrane conductance regulator. Login to comment
147 Among the eight novel mutations identified, p.Ser118Pro, p.Met281Arg, p.Gly126Cys, p.Arg933Thr were predicted to be damaging, whereas p.Arg518Lys, p.Ala141Gly, p.His139Gln, p.Glu585Gln were possibly neutral mutations (http://genetics.bwh.harvard.edu/ pph2/). Login to comment