ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2834C>T (p.Ser945Leu) (rs397508442)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056372 SCV000071530 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000660828 SCV000783067 drug response ivacaftor response - Efficacy 2018-03-26 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.
Counsyl RCV000056372 SCV000220296 pathogenic Cystic fibrosis 2014-05-08 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723381 SCV000226578 pathogenic not provided 2015-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056372 SCV000696927 pathogenic Cystic fibrosis 2019-01-23 criteria provided, single submitter clinical testing Variant summary: CFTR c.2834C>T (p.Ser945Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of 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 7.6e-05 in 277138 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (7.6e-05 vs 0.013), allowing no conclusion about variant significance. c.2834C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. One ClinVar submission from PharmGKB reports the variant to have a drug response. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000056372 SCV000886264 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000723381 SCV000889300 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004489 SCV001163534 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009364 SCV001169217 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
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000723381 SCV001251894 pathogenic not provided 2020-05-03 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000723381 SCV001449638 pathogenic not provided 2016-04-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286193 SCV001472724 pathogenic none provided 2019-11-25 criteria provided, single submitter clinical testing The CFTR c.2834C>T; p.Ser945Leu variant (rs397508442) is reported in the literature in multiple individuals affected with either pancreatic sufficient or pancreatic insufficient cystic fibrosis (CF) (see link to CFTR2 database, Sosnay 2013), and also in a few individuals affected with CFTR-related disorders who carry a second pathogenic-mild variant or no reported second variant (Masvidal 2009, Masson 2013). The p.Ser945Leu variant is reported in ClinVar (Variation ID: 53575), and is found in the general population with an overall allele frequency of 0.0071% (20/282808 alleles) in the Genome Aggregation Database. The serine at codon 945 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show reduced processing, maturation and chloride transport activity (Sosnay 2013, Van Goor 2014). Both in vitro and in vivo functional analyses demonstrate a positive response to drug treatment for CF patients (Kim 2018, Van Goor 2014). Based on available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: Claustres M et al. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France. Hum Mol Genet. 1993 Aug;2(8):1209-13. Kim J et al. Ivacaftor restores CFTR-dependent sweat gland fluid secretion in cystic fibrosis subjects with S945L alleles. J Cyst Fibros. 2018 Mar;17(2):179-185. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. Masvidal L et al. The p.Arg258Gly mutation in intracellular loop 2 of CFTR is associated with CFTR-related disorders. Genet Test Mol Biomarkers. 2009 13(6):765-8. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 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.
Invitae RCV000056372 SCV001578418 pathogenic Cystic fibrosis 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 945 of the CFTR protein (p.Ser945Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs397508442, ExAC 0.03%). This variant has been observed in individuals affected with cystic fibrosis (PMID: 16189704, 19318346, 21354377, 29279204, 29504914). ClinVar contains an entry for this variant (Variation ID: 53575). This variant has been reported to affect CFTR protein function (PMID: 22545782, 23891399, 29279204). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000056372 SCV001711961 pathogenic Cystic fibrosis 2021-06-03 criteria provided, single submitter clinical testing
Natera, Inc. RCV001027913 SCV001190636 pathogenic CFTR-related disorders 2019-05-20 no assertion criteria provided clinical testing

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