ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.349C>T (p.Arg117Cys) (rs77834169)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056382 SCV000071518 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Invitae RCV000056382 SCV000074928 pathogenic Cystic fibrosis 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 117 of the CFTR protein (p.Arg117Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs77834169, ExAC 0.06%). This variant has been reported in individuals with cystic fibrosis( CF) with or without pancreatic insufficiency (PMID: 21783433, 23974870, 7525450, 22658665, 15482777, 24586523). This variant has also been reported in male individuals with congenital bilateral absence of the vas deferens (PMID: 7529962, 21520337, 15482777) and individuals with a mild form of CF (PMID: 11788090). ClinVar contains an entry for this variant (Variation ID: 48688). Functional studies have shown this variant results in a significant decrease in chloride channel conductance (PMID: 23974870, 238191399, 20932301, 18449561). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000056382 SCV000485264 pathogenic Cystic fibrosis 2015-11-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727627 SCV000854903 pathogenic not provided 2017-12-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000042 SCV000883564 pathogenic not specified 2018-10-04 criteria provided, single submitter clinical testing The CFTR c.349C>T, p.Arg117Cys variant has been reported in multiple individuals with cystic fibrosis (Claustres 2000, Costa 2011, Gonska 2009, McGinniss 2005, Sosnay 2013, Strandvik 2001, Wong 2004), and is often associated with pancreatic sufficiency (Sosnay 2013, CFTR2 database) and borderline sweat chloride (Lebecque 2002, Sontag 2005, Wong 2004). However, the variant has also been identified in patients with CFTR-related disorders, such as congenital bilateral absence of vas deferens (Claustres 2000, Mercier 1995, Steiner 2011, Wilschanski 2006, Zielenski 1995). Functional characterization of the variant protein indicates a defect in chloride transport (Sosnay 2013, van Goor 2014) likely due to instability of the open CFTR channel (Cui 2014, Hammerle 2001) or defect in attracting extracellular chloride ions (Zhou 2008). Based on the above information, the variant is classified as moderately pathogenic. REFERENCES CFTR2 database: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000; 16(2):143-56. Costa C et al. A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice. J Cyst Fibros. 2011; 10(6):479-82. Cui G et al. Three charged amino acids in extracellular loop 1 are involved in maintaining the outer pore architecture of CFTR. J Gen Physiol. 2014; 144(2):159-79. Gonska T et al. Sweat gland bioelectrics differ in cystic fibrosis: a new concept for potential diagnosis and assessment of CFTR function in cystic fibrosis. Thorax. 2009; 64(11):932-8. Hammerle M et al. Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability. J Biol Chem. 2001; 276(18):14848-54. Lebecque P et al. Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children. Am J Respir Crit Care Med. 2002; 165(6):757-61. McGinniss MJ et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005 Dec;118(3-4):331-8. Mercier B et al. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients. Am J Hum Genet. 1995; 56(1):272-7. Sontag MK et al. Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes. J Pediatr. 2005 Sep;147(3 Suppl):S83-8. 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. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. Strandvik B et al. Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. Genet Test. 2001; 5(3):235-42. 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. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. Wong L et al. The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization. Fertil Steril. 2004; 82(4):947-9. Zielenski J et al. CFTR gene variant for patients with congenital absence of vas deferens. Am J Hum Genet. 1995; 57(4):958-60. Zhou J et al. Identification of positive charges situated at the outer mouth of the CFTR chloride channel pore. Pflugers Arch. 2008; 457(2):351-60.
Mendelics RCV000056382 SCV000886205 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000727627 SCV000888087 pathogenic not provided 2018-07-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763150 SCV000893737 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
Illumina Clinical Services Laboratory,Illumina RCV000056382 SCV000916175 pathogenic Cystic fibrosis 2019-01-11 criteria provided, single submitter clinical testing Across a selection of the available literature, the CFTR c.349C>T (p.Arg117Cys) missense variant has been identified in a total of 17 individuals, including in a homozygous state in three with cystic fibrosis (CF) and in a compound heterozygous state in 11 with CF and three individuals with congenital bilateral absence of the vas deferens (CBAVD) (Dörk et al. 1994; Massie et al. 2001; Wilschanski et al. 2006; Steiner et al. 2011; Costa et al. 2011; Schippa et al. 2013; Ziętkiewicz et al. 2014; Lundman et al. 2016). The p.Arg117Cys variant was frequently found in trans with p.Phe508del variant. The p.Arg117Cys variant is also reported in 141 individuals in the CFTR2 database ( Control data are unavailable for this variant, which is reported at a frequency of 0.000388 in the European (non-Finnish) population of the Genome Aggregation Database. Sosnay et al. (2013) and Van Goor et al. (2014) demonstrated that the p.Arg117Cys variant resulted in significantly reduced chloride ion conductance and transport, as compared to wild type. The pathogenicity of the p.Arg117Cys variant is affected by a specific intronic variation in CFTR, termed the poly-T tract, which occurs in three forms (5T/7T/9T). Depending on which poly-T form is present in the same copy of the CFTR gene with p.Arg117Cys, differing clinical outcomes may occur. Based on the evidence, the p.Arg117Cys variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV001004428 SCV001163472 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing

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