ABCC7 p.Arg297Trp
ClinVar: |
c.890G>A
,
p.Arg297Gln
N
, Benign/Likely benign
c.889C>T , p.Arg297Trp ? , not provided |
CF databases: |
c.889C>T
,
p.Arg297Trp
(CFTR1)
?
, Missense mutation R297W was identified in a Vietnamese CBAVD patient who is heterozygous for R297W and for the 5T allele. Both chromosomes also carry the Q1352H missense variant in exon 22.
c.890G>A , p.Arg297Gln (CFTR1) ? , This charge from a basic to an uncharged amino acid is probably consistent with disease and the mutation occurs at a CG dinucleotide, a known mutation hot spot. This mutation was detected in 2 sibs with CF and is associated with an X2 K1 haplotype, the other mutation in this family is also on a X2 K1 haplotype and is undefined. In the original report, R297Q was not detected in a further 54 CF chromosomes with an unidefined mutations and 50 normal chromosomes, all samples were of Northern Irish origin. Dubourg argued that R297Q is a rare polymorphism rather than a deleterious mutation as usually reported. The first supportive evidence came from a family where R297Q was associated with two of the most severe molecular defects DF508 or N1303K on healthy subjects (DORVAL, JEZEQUEL, CHAUVEL, DUBOURG et al. (1995) Human Mutation, 6 : 334-335). More recently, Dubourg et al. identified the same aminoacid change (R297Q) in association with the 574delA mutation in an healthy subject. (Christèle DUBOURG, Laboratoire de GENETIQUE MOLECULAIRE, CHRU PONTCHAILLOU, 35033 RENNES Cedex FRANCE; Tel : 33.2.99.28.41.31; Fax : 33.2.99.28.41.85; E-mail : blayau@sunaimed.univ-rennes1.fr ) |
Predicted by SNAP2: | A: D (91%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (91%), I: D (91%), K: D (71%), L: D (91%), M: D (85%), N: D (95%), P: D (95%), Q: D (63%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (95%), |
Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: N, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Genetic prevalence and characteristics in children... J Pediatr Gastroenterol Nutr. 2012 May;54(5):645-50. Sultan M, Werlin S, Venkatasubramani N
Genetic prevalence and characteristics in children with recurrent pancreatitis.
J Pediatr Gastroenterol Nutr. 2012 May;54(5):645-50., [PMID:22094894]
Abstract [show]
AIMS: The causes of chronic (CP) and recurrent acute pancreatitis (RAP) in children include anatomic abnormalities and hereditary, metabolic, and autoimmune disorders, with a significant proportion of cases being labeled as idiopathic. Genetic pancreatitis (GP) is associated with mutations of cystic fibrosis transmembrane conductor regulator gene (CFTR), cationic trypsinogen (PRSS1) gene, and serine protease inhibitor Kazal type 1 (SPINK1). There literature is sparse regarding the clinical profile of GP in children. The aim of the present study was to estimate the prevalence and describe the clinical characteristics and outcome of genetic pancreatitis. METHODS: We reviewed the charts of children ages 18 years or younger with RAP or CP diagnosed from 2000 to 2009 at the Children's Hospital of Wisconsin, Milwaukee. Twenty-nine patients with RAP or CP were identified, of whom 23 (79%) were positive for mutations in >/=1 of the above-mentioned genes, and were included for review. RESULTS: The median age of symptom onset was 5 years (range 9 months-15 years) with diagnosis at 6.5 years (range 1-16 years). Twenty-one were white; 14 were girls. The most common presenting symptoms were abdominal pain and vomiting. Patients with RAP had 2 to 8 episodes of pancreatitis during 3.6-year average follow-up. Family history was positive in 5 of 29 of gene-tested patients. CFTR, SPINK1, or PRSS1 mutations were seen in 14 (48%), 8 (27%), and 7 (24%) patients, respectively. Two patients were homozygous for CFTR mutations, 6 heterozygote and 4 patients had 5 T variants. Two other patients had double heterozygous mutations in F508 del/2789 + 5G > A and F508 del/5T variant. Six patients with CP had a combination of CFTR and SPINK1 or PRSS1 mutations. Eleven of 29 (38%) patients met radiological criteria for CP. All of the heterozygote patients with a combination of CFTR and SPINK1 or PRSS1 mutations had CP. Eight patients developed a chronic pain syndrome and 2 developed exocrine pancreatic insufficiency during follow-up. CONCLUSIONS: We found a high prevalence of genetic mutations in patients without anatomic or metabolic abnormalities known to be associated with pancreatitis. Studies are needed to ascertain the genetic causes of RAP and CP and examine the relation between single CFTR mutations and single mutations in the PRSS1 and SPINK1 genes.
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No. Sentence Comment
78 Six patients were heterozygous for the CFTR mutation (F508del, R297W, D1152H, R297Q, and I148T).
X
ABCC7 p.Arg297Trp 22094894:78:63
status: NEW[hide] Distinct spectrum of CFTR gene mutations in congen... Hum Genet. 1997 Sep;100(3-4):365-77. Dork T, Dworniczak B, Aulehla-Scholz C, Wieczorek D, Bohm I, Mayerova A, Seydewitz HH, Nieschlag E, Meschede D, Horst J, Pander HJ, Sperling H, Ratjen F, Passarge E, Schmidtke J, Stuhrmann M
Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens.
Hum Genet. 1997 Sep;100(3-4):365-77., [PMID:9272157]
Abstract [show]
Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%-2% of male infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the "5T" allele, on both chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD patients was homozygous for delta F508 and none was compound heterozygous for delta F508 and a nonsense or frameshift mutation. Instead, homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions. Twenty-one German CAVD patients were compound heterozygous for delta F508 and R117H, which was the most frequent CAVD genotype in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense variants, such as F508C or 1716 G-->A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.
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No. Sentence Comment
81 The R297W mutation was identified on a Q1352H chromosome in a Vietnamese CBAVD patient (see below).
X
ABCC7 p.Arg297Trp 9272157:81:4
status: NEW86 The V938G substitution was identified in two unrelated patients, one homozygote with unilateral ab- 368 Table 1A Frequency distribution and haplotypes of CFTR mutations in 106 CAVD patients Mutationa Nucleotide changesb Locationc Frequencyd Haplotypee Referencef 174delA deletion of A at 174 exon 1 1 D3 This study E56K G→A at 298 exon 3 1 B3 This study D58N G→A at 304 exon 3 1 C2 This study D110H G→A at 460 exon 4 2 C2 Dean et al. (1990) R117H G→A at 482 exon 4 24 B6 Dean et al. (1990) A120T G→A at 490 exon 4 1 n.p. Chillón et al. (1994) ̃L138 insertion of CTA after 546 exon 4 1 A2 This study L206W T→G at 749 exon 6a 1 B8 Claustres et al. (1993) M265R T→G at 926 exon 6b 1 A2 Schwarz et al. (pers. comm.) R297W C→T at 1021 exon 7 1 C2 This study 1078delT deletion of T at 1078 exon 7 1 C2 Claustres et al. (1992) R334W C→T at 1132 exon 7 1 B1 Gasparini et al. (1991) R334L G→T at 1133 exon 7 1 D3 This study I336K T→A at 1139 exon 7 1 A2 Cuppens et al. (1993) R347H G→A at 1172 exon 7 3 D1 Cremonesi et al. (1992) L375F A→C at 1257 exon 8 1 B3 Jézéquel et al. (1996) ∆F508 deletion of 3 bp between 1652-1655 exon 10 57 B1 Kerem et al. (1989) G542X G→T at 1756 exon 11 2 B1 Kerem et al. (1990) R553X C→T at 1789 exon 11 1 A4 Cutting et al. (1990) L568F G→T at 1836 exon 12 1 B3 This study 2184insA insertion of A at 2184 exon 13 1 D3 Dörk et al. (1994b) 2789+5 G→A G→A at 2789+5 intron 14b 4 D3 Highsmith et al. (1997) R933S A→T at 2931 exon 15 1 n.p.
X
ABCC7 p.Arg297Trp 9272157:86:774
status: NEW91 R. Knowles, Q1352H by T. Nukiwa and K. Seyama are indicated g Missense substitutions R933S and R75Q occurred together in a ∆F508 heterozygous patient h Q1352H is associated with 5T and R297W, respectively i Missense substiutions G576A and R668C are linked on the same allele in both CBAVD patients sence of the vas deferens (CUAVD) and one heterozygote with CBAVD.
X
ABCC7 p.Arg297Trp 9272157:91:192
status: NEW132 This male was homozygous for a missense mutation, Q1352H, in exon 22 of the CFTR gene, but heterozygous for a "5T" allele and for the novel R297W missense mutation.
X
ABCC7 p.Arg297Trp 9272157:132:140
status: NEW137 Complex alleles are indicated a One CF allele with R75X and 125G→C b One CBAVD allele with R75Q and R933S c One CBAVD allele with 5T and Q1352H d Two CF alleles with F508C and S1251N e One CF allele with 1716G→A and L619S f G576A and R668C were linked on two CBAVD and three CF alleles, whereas two additional CF alleles carried R668C together with the 3849+10kB C→T mutation (Dörk and Stuhrmann 1995) 371 Table 3 CFTR mutation genotypes in 106 males with CAVD Genotype PolyT Frequency Ethnic descent Diagnosis ∆F508/R117H 9/7 21 German, Austrian 20 CBAVD, 1 CUAVD ∆F508/5T 9/5 9 German, Austrian 8 CBAVD, 1 CUAVD ∆F508/F508C 9/7 3 German CBAVD ∆F508/R347H 9/9 2 German CBAVD ∆F508/1716 G→A 9/7 2 German CBAVD ∆F508/3272-26 A→G 9/7 2 German CBAVD ∆F508/E56K 9/7 1 German CBAVD ∆F508/M265R 9/7 1 German-Portuguese CBAVD ∆F508/R334W 9/9 1 German CBAVD ∆F508/T351S 9/9 1 German CBAVD ∆F508/L375F 9/7 1 Volga German CBAVD ∆F508/G576A & R668C 9/7 1 German CBAVD ∆F508/R933S 9/7 1 German CBAVD ∆F508/L997F 9/9 1 German CBAVD ∆F508/Y1032C 9/7 1 German CBAVD ∆F508/D1152H 9/7 1 German CBAVD ∆F508/K1351E 9/7 1 German CBAVD ∆F508/D1377H 9/7 1 Portuguese CBAVD ∆F508/L1388Q 9/7 1 German CBAVD ∆F508/unknown 9/7 4 German 3 CBAVD, 1 CUAVD 5T/5T 5/5 2 German CBAVD 5T/G542X 5/9 2 German, Turkish CBAVD 5T/D58N 5/7 1 Lebanese CBAVD 5T/̃L138 5/7 1 German-Polish CBAVD 5T/1078delT 5/7 1 German CBAVD 5T/R553X 5/7 1 German CBAVD 5T/2184insA 5/7 1 Turkish CBAVD 5T/D979A 5/7 1 Vietnamese CBAVD 5T/D1152H 5/7 1 Turkish CBAVD 5T/3659delC 5/7 1 German CBAVD 5T/S1235R 5/7 1 Greek CBAVD 5T/W1282X 5/7 1 German CBAVD 5T & Q1352H/ R297W & Q1352H 5/7 1 Vietnamese CBAVD 5T/unknown 5/7 1 German CBAVD R117H/L206W 7/9 1 German CBAVD R117H/2789+5 G→A 7/7 1 German CBAVD R117H/unknown 7/7 1 German CBAVD 2789+5 G→A/2789+5 G→A 7/7 1 Lebanese CBAVD 2789+5 G→A/L973F 7/7 1 German CBAVD V938G/V938G 7/7 1 Greek CBAVD V938G/174delA 7/7 1 German CBAVD D110H/D110H 7/7 1 Turkish CBAVD R334L/I336K 7/7 1 German CBAVD R347H/N1303K 9/9 1 German CBAVD L568F/D1152H 7/7 1 Turkish CBAVD 3272-26 A→G/V1153E 7/7 1 German CBAVD R75Q/unknown 7/7 1 German CBAVD A120T/unknown 9/7 1 German CBAVD 1716G→A/unknown 7/7 1 German CBAVD G576A & R668C/unknown 7/7 1 German CBAVD 2752-15 C→G/unknown 7/7 1 Iranian CBAVD Unknown/unknown 17 German, Turkish 7 CBAVD and 1 CUAVD without observed renal agenesis, 9 CBAVD with renal agenesis allele and the R297W mutation on a homozygous Q1352H background may then reduce CFTR function to a disease-causing level.
X
ABCC7 p.Arg297Trp 9272157:137:1794
status: NEWX
ABCC7 p.Arg297Trp 9272157:137:2632
status: NEW