ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4357C>T (p.Arg1453Trp) (rs4148725)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456157 SCV000552135 uncertain significance Cystic fibrosis 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1453 of the CFTR protein (p.Arg1453Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs4148725, ExAC 0.2%). This variant has been reported in individuals affected with pancreatitis and unaffected control individuals with similar frequencies (PMID: 17003641, 22664493, 26089335, 25492507, 15121783). It has not been reported in the literature (PMID: 23974870) or databases (www.cftr2.org) to cause cystic fibrosis (CF) or congenital absence of vas deferences (CAVD). ClinVar contains an entry for this variant (Variation ID: 411121). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A single experimental study reported a small decrease (~37%) in chloride channel activity associated with this missense variant (PMID: 12952861), but the clinical relevance of this effect is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507912 SCV000601122 uncertain significance not provided 2020-03-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001002200 SCV000697024 uncertain significance not specified 2020-07-14 criteria provided, single submitter clinical testing 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. Six 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. one calling it pathogenic, four as a VUS, and one as likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000507912 SCV000858814 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
Mendelics RCV000456157 SCV001137501 uncertain significance Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283265 SCV001160073 uncertain significance none provided 2020-02-20 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001160218 SCV001322001 likely benign CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000507912 SCV001714850 uncertain significance not provided 2020-12-02 criteria provided, single submitter clinical testing

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