chr7-117667022-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_000492.4(CFTR):c.4357C>T(p.Arg1453Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,614,034 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CFTR | NM_000492.4 | c.4357C>T | p.Arg1453Trp | missense_variant | Exon 27 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251036Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135632
GnomAD4 exome AF: 0.000390 AC: 570AN: 1461760Hom.: 6 Cov.: 31 AF XY: 0.000396 AC XY: 288AN XY: 727188
GnomAD4 genome AF: 0.000236 AC: 36AN: 152274Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:6
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The CFTR c.4357C>T; p.Arg1453Trp variant (rs4148725) is reported in the literature in individuals with chronic pancreatitis and bronchiectasis, as well as in control individuals (Keiles 2006, Kondo 2015, Lee 2003, Nakano 2015). While one study reported significant enrichment of this variant in individuals with idiopathic pancreatitis (Kondo 2015), this study included a small number of subjects, and a second study did not observe significant enrichment among pancreatitis patients (Nakano 2015). The p.Arg1453Trp variant is reported in ClinVar (Variation ID: 411121) and is found in the East Asian population with an allele frequency of 0.1% (20/19892 alleles) in the Genome Aggregation Database. The arginine at codon 1453 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, chloride channel activity assays suggest that the p.Arg1453Trp variant exhibits a substantially reduced probability of opening, though this results in only a mild reduction in channel current (Lee 2003). Due to limited information, the clinical significance of the p.Arg1453Trp variant is uncertain at this time. References: Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Kondo S et al. Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. Lee JH et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003 Sep 15;12(18):2321-32. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015 May;60(5):1297-307. -
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Observed in individuals with pancreatitis or bronchiectasis as well as in healthy controls (Lee et al., 2003; Fujiki et al., 2004; Keiles et al., 2006; Aoyagi et al., 2009; Kondo et al., 2015; Nakano et al., 2015; Iso et al., 2019; Fujita et al., 2022; Ni et al., 2022); Published functional studies demonstrate reduced channel opening probability, normal gene expression and splicing, and no significant effect on cAMP-activated anion exchange (Lee et al., 2003; Iso et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.4489C>T; This variant is associated with the following publications: (PMID: 20981092, 34996830, 35387941, 12952861, Jefri[thesis]2018, 20571109, Yoshimura[abstract]2012, 26089335, 25492507, 30992994, 22664493, 20879059, 19383231, 11504857, 17003641, 15121783, 12166651, 35313924, 22515107) -
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CFTR-related disorder Uncertain:4Benign:1
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The CFTR c.4357C>T variant is predicted to result in the amino acid substitution p.Arg1453Trp. This variant has been reported in patients with idiopathic pancreatitis or bronchitis from Japan and Korea as well as in healthy individuals (Kondo et al. 2015. PubMed ID: 26089335; Kim et al. 2010. PubMed ID: 20879059; Lee et al. 2003. PubMed ID: 12952861). However, this variant does not appear to affect CFTR protein expression and results are conflicting on whether chloride channel activity is affected (Lee et al. 2003. PubMed ID: 12952861). This variant is reported in 0.10% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, the clinical significance of this variant is classified as uncertain at this time due to insufficient functional and genetic evidence. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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Cystic fibrosis Uncertain:3Benign:1
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The p.R1453W variant (also known as c.4357C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4357. The arginine at codon 1453 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was observed in a Korean patient with bronchiectasis, but also in two healthy control individuals. The authors demonstrated that although this variant had no effect on the expression of the protein, there was a reduction in chloride channel function (Lee JH, et al. Hum Mol Genet. 2003;12(18):2321-2332). This variant has been observed in multiple Japanese cohorts of individuals diagnosed with pancreatitis (Fujiki K et al. J Med Genet. 2004;41(5):e55; Kondo S et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2015 Aug;309:G260-9; Iso M et al. Hum Genome Var, 2019 Apr;6:17; Fujita S et al. Endocr J, 2022 Sep;69:1101-1108). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
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not specified Uncertain:1
Variant summary: CFTR c.4357C>T (p.Arg1453Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 258140 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the maximum expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.0011 vs 0.013), allowing no conclusion about variant significance. However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0232 (in the jMorp database). This frequency is about 1.7-fold higher than the maximum expected for a pathogenic variant, suggesting the variant could be a benign polymorphism. Though the variant, c.4357C>T, has not been reported in the literature in individuals affected with Cystic Fibrosis (CF) or Congenital Bilateral Absence of the Vas Deferens (CBAVD), it was found in several Japanese patients with pancreatitis, and was also described in some patients affected with diffuse panbronchiolitis, bronchiectasis and asthma. These reports do not provide unequivocal conclusions about association of the variant with the reported disease phenotypes. In two Japanese case-control studies, this variant was not significantly overrepresented in pancreatitis patient cohorts compared to controls (Fujiki_2004, Nakano_2015). In two other studies however, the frequency of this variant was higher in pancreatitis patients than in controls, though the sample sizes were small (Kondo_2015, Iso_2019). Therefore, whether this variant is a risk variant to pancreatitis needs to be further investigated. In one ICP patient, this variant co-occurred with another pathogenic variant (c.194+2T>C) and a risk variant (c.101A>G/p.Asn34Ser) in the SPINK1 gene (Nakano_2015), suggesting this variant was not a primary cause of disease in the patient. One functional study has shown that this variant leads to 37% decrease in whole cell chloride currents due to significantly reduced (by 78%) channel opening probability (Lee_2003), but the clinical significance of this effect on the associated pathophysiology of disease is unclear. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. six as a VUS, and one as likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary pancreatitis Uncertain:1
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Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at