ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.617T>G (p.Leu206Trp) (rs121908752)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000007611 SCV000071508 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000660772 SCV000783011 drug response ivacaftor response - Efficacy 2018-03-22 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079011 SCV000231548 pathogenic not provided 2015-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000079011 SCV000512573 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing The L206W variant in the CFTR gene has been reported previously in individuals with CFTR-related disorders who also harbor additional variants in the CFTR gene (Clain et al., 2005; Claustres et al., 1993). The L206W variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L206W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In vitro studies of the L206W variant demonstrate significant reduction in CFTR processing in HeLa cells resulting in a decrease in protein production at the cell surface compared to wild type cells (Clain et al., 2005; Van Goor et al., 2014). A missense variant in the same residue (L206F) has been reported previously in association with a CFTR-related disorder (Claustres et al., 2000), supporting the functional importance of this region of the protein. We interpret L206W as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999852 SCV000603055 pathogenic none provided 2020-04-16 criteria provided, single submitter clinical testing The CFTR c.617T>G; p.Leu206Trp variant (rs121908752) is reported in the literature in individuals affected with a pancreatic-sufficient form of cystic fibrosis (Bernardino 2000, Clain 2005, de Garcia 2005, Gallati 2009, Ooi 2012, Sosnay 2013, CFTR2 database). Functional characterization of the variant indicates defects in processing and maturation of the CFTR protein (Clain 2005, Sosnay 2013, van Goor 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 7190), and is found in the general population with an overall allele frequency of 0.018% (51/282,838 alleles) in the Genome Aggregation Database. The leucine at codon 206 is highly conserved, and computational analyses (PolyPhen-2, SIFT) predict that the variant is deleterious. Based on available information, the p.Leu206Trp variant is considered to be pathogenic. References: CFTR2 database: Bernardino A et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000; 4(1):69-74. Clain J et al. Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype. Hum Mutat. 2005; 25(4):360-71. de Garcia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005; 60(7):558-63. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. 2013; Nat Genet. 45(10):1160-7. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007611 SCV000697039 pathogenic Cystic fibrosis 2017-08-18 criteria provided, single submitter clinical testing Variant summary: c.617T>G affects a conserved nucleotide, resulting in amino acid change from Leu to Trp. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 27/121506 control chromosomes at a frequency of 0.0002222, which does not exceed the maximal expected frequency of a pathogenic allele (0.0129603). This variant has been reported in multiple CF patients worldwide. Functional studies showed the variant of interest with only about 5% of WT level of [Cl-] transport and defective CFTR processing and maturation (Sosnay_2013 and Van Goor_2014). In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic.
Mendelics RCV000007611 SCV000886193 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000079011 SCV000889314 pathogenic not provided 2015-11-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763156 SCV000893743 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004443 SCV001163488 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000007611 SCV001167220 pathogenic Cystic fibrosis 2019-10-04 criteria provided, single submitter clinical testing Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See for phenotype information.
CFTR-France RCV001009388 SCV001169241 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Myriad Women's Health, Inc. RCV000007611 SCV001194077 pathogenic Cystic fibrosis 2019-11-12 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.617T>G(L206W) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23974870, 15776432, and 18456578. Classification of NM_000492.3(CFTR):c.617T>G(L206W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079011 SCV001250500 pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing
Invitae RCV000007611 SCV001580373 pathogenic Cystic fibrosis 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with tryptophan at codon 206 of the CFTR protein (p.Leu206Trp). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and tryptophan. This variant is present in population databases (rs121908752, ExAC 0.05%). This variant has been reported in combination with a second pathogenic CFTR variant in numerous individuals affected with cystic fibrosis (CF) and/or congenital bilateral absence of the vas deferens (CBAVD) (PMID: 15776432, 21520337, 23974870, 20021716, 27086061). This variant has also been observed in individuals with chronic pancreatitis (PMID: 23951356, 23751316). ClinVar contains an entry for this variant (Variation ID: 7190). Experimental studies have shown that this missense change causes reduced CFTR processing, chloride ion channel conductance, and altered subcellular localization in vitro (PMID: 15776432, 23891399). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000079011 SCV001715946 pathogenic not provided 2019-07-29 criteria provided, single submitter clinical testing
OMIM RCV000007611 SCV000027812 pathogenic Cystic fibrosis 2005-04-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000007611 SCV000536746 pathogenic Cystic fibrosis 2016-04-21 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000079011 SCV001739691 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000079011 SCV001952464 pathogenic not provided no assertion criteria provided clinical testing

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