ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.617T>G (p.Leu206Trp) (rs121908752)

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Total submissions: 12
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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
Counsyl RCV000007611 SCV000485228 pathogenic Cystic fibrosis 2016-02-02 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 RCV000079011 SCV000603055 pathogenic not provided 2017-05-17 criteria provided, single submitter clinical testing The CFTR c.617T>G, p.Leu206Trp variant (rs121908752) has been observed in patients diagnosed 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). The variant is listed in ClinVar (Variation ID: 7190), and observed in the general population databases at a frequency of 0.023 percent in the Exome Variant Server, and 0.018 percent in the Genome Aggregation Database. The leucine at residue 206 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as moderately pathogenic. REFERENCES CFTR2 database: http://cftr2.org/ 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. 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.
Integrated Genetics/Laboratory Corporation of America 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 absence of the vas deferens 2018-10-31 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

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