ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1000C>T (p.Arg334Trp) (rs121909011)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000007559 SCV000071388 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000007559 SCV000071519 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Invitae RCV000007559 SCV000074204 pathogenic Cystic fibrosis 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 334 of the CFTR protein (p.Arg334Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is a common cause of Cystic Fibrosis (CF) (PMID: 15371902), reported in combination with a pathogenic CFTR variant in more than 500 affected individuals ( Furthermore, functional experiments demonstrate that the chloride conductance of this missense change is only ~1% of normal activity (PMID: 23974870). For these reasons, this variant has been classified as Pathogenic.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224060 SCV000281464 pathogenic not provided 2015-02-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000033 SCV000603018 pathogenic not specified 2019-02-08 criteria provided, single submitter clinical testing The CFTR c.1000C>T; p.Arg334Trp variant (rs121909011) is reported in numerous individuals affected with cystic fibrosis and is often associated with pancreatic sufficiency (Antinolo 1997, Ooi 2012, Sosnay 2013, CFTR2 database). Many affected individuals have been reported to carry an additional pathogenic variant in trans (Antinolo 1997). Functional characterization of p.Arg334Trp variant protein indicates substantial defects in chloride transport activity (Sosnay 2013, Van Goor 2014). This variant is reported as pathogenic in ClinVar (7139), and it is found in the general population with an overall allele frequency of 0.006% (16/282602 alleles) in the Genome Aggregation Database. The arginine at codon 334 is highly conserved, and computational algorithms (SIFT, PolyPhen2) predict this variant to be damaging to the protein. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: Antinolo G et al. Genotype-phenotype relationship in 12 patients carrying cystic fibrosis mutation R334W. J Med Genet. 1997 Feb;34(2):89-91. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;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 Jan;13(1):29-36.
Institute of Human Genetics,Klinikum rechts der Isar RCV000007559 SCV000680167 pathogenic Cystic fibrosis 2017-09-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000007559 SCV000696813 pathogenic Cystic fibrosis 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The CFTR c.1000C>T (p.Arg334Trp) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 8/121330 (1/15174), which does not exceed the estimated maximal expected allele frequency for a pathogenic CFTR variant of 1/77. The variant of interest has been reported by multiple affected individuals and has been established as a common disease variant, along with being indicated to be on the ACMG variant report list. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000007559 SCV000746379 pathogenic Cystic fibrosis 2017-12-03 criteria provided, single submitter clinical testing
Mendelics RCV000007559 SCV000886179 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763567 SCV000894406 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000224060 SCV001134105 pathogenic not provided 2019-08-11 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Baylor Genetics RCV001004246 SCV001163122 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000007559 SCV001169454 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Myriad Women's Health, Inc. RCV000007559 SCV001193984 pathogenic Cystic fibrosis 2019-12-20 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1000C>T(R334W) is classified as pathogenic and is a non-classic variant in the context of cystic fibrosis. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.1000C>T(R334W) 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.
OMIM RCV000007559 SCV000027760 pathogenic Cystic fibrosis 1997-02-01 no assertion criteria provided literature only

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