Submissions for variant NM_000492.4(CFTR):c.349C>T (p.Arg117Cys)

dbSNP: rs77834169

Total submissions: 26

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
PharmGKB	RCV003227627	SCV003925514	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056382	SCV000074928	pathogenic	Cystic fibrosis	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 117 of the CFTR protein (p.Arg117Cys). This variant is present in population databases (rs77834169, gnomAD 0.04%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens and/or cystic fibrosis (PMID: 7525450, 7529962, 11788090, 15482777, 21520337, 21783433, 22658665, 23974870, 24586523). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48688). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 18449561, 20932301, 23891399, 23974870). 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
Eurofins Ntd Llc (ga)	RCV000727627	SCV000854903	pathogenic	not provided	2017-12-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727627	SCV000883564	pathogenic	not provided	2023-04-25	criteria provided, single submitter	clinical testing	The CFTR c.349C>T; p.Arg117Cys variant (rs77834169) is reported in the literature in multiple individuals affected 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, this 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), and in asymptomatic individuals even when found with another pathogenic variant on the opposite chromosome (Wong 2004). This variant is reported in ClinVar (Variant ID: 48688), and is found in the general population with an overall allele frequency of 0.018% (52/282344 alleles) in the Genome Aggregation database. Computational analyses predict that this variant is deleterious (REVEL: 0.823). Functional characterization of the variant protein indicates a defect in chloride transport (Cui 2014, Sosnay 2013, van Goor 201408). Based on available information, this variant is considered to be pathogenic with varying clinical consequences. References: CFTR2 database: http://cftr2.org/ 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. PMID: 10923036. 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. PMID: 21783433. 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. PMID: 25024266. 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. PMID: 19734129. 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. PMID: 11897640. 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. PMID: 7529962. Parad R et al. Diagnostic dilemmas resulting from the immunoreactive trypsinogen/DNA cystic fibrosis newborn screening algorithm. J Pediatr. 2005; 147(3 Suppl):S78-82. PMID: 16202789. 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. PMID: 23974870. 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. PMID: 21520337. 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. PMID: 11788090. Wilschanski M et al. Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations. J Pediatr. 1995; 127(5):705-10. PMID: 7472820. 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. PMID: 15482777. Zielenski J et al. CFTR gene variant for patients with congenital absence of vas deferens. Am J Hum Genet. 1995; 57(4):958-60. PMID: 7573058.
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	2023-07-20	criteria provided, single submitter	clinical testing	The CFTR c.349C>T (p.Arg117Cys) variant has been reported in the published literature in compound heterozygous individuals with classic CF (PMIDs: 31523618 (2019), 24586523 (2014), 21783433 (2011), 11788090 (2001), 7525450 (1994)), and CFTR-related disorders (PMIDs: 28801929 (2017), 22658665 (2012), 21520337 (2011), 7529962 (1995)). In addition, functional studies indicate this variant has deleterious effects on CFTR protein processing and chloride channel conductance (PMIDs: 23891399 (2014), 23974870 (2013), 20932301 (2010)). The frequency of this variant in the general population, 0.0015 (38/26094 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
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	2024-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 (http://cftr2.org/). 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
CFTR-France	RCV001009394	SCV001169247	pathogenic	Cystic fibrosis; CFTR-related disorder	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	RCV000056382	SCV001251845	pathogenic	Cystic fibrosis	2020-05-03	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000727627	SCV001450239	pathogenic	not provided	2014-07-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000056382	SCV001810330	pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000056382	SCV002507394	pathogenic	Cystic fibrosis	2019-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056382	SCV002612924	pathogenic	Cystic fibrosis	2021-11-30	criteria provided, single submitter	clinical testing	The p.R117C pathogenic mutation (also known as c.349C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 349. The arginine at codon 117 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first described in a 12-year-old cystic fibrosis (CF) patient with elevated sweat chloride levels and pancreatic sufficiency, who was confirmed to carry a pathogenic CFTR mutation on the other allele (Dörk T et al. Hum Genet. 1994;94(5):533-42). In one study in the Swedish population, this mutation was identified in 7 patients with elevated sweat chloride levels and pancreatic sufficiency (PS); each had p.F508del on the other chromosome (in trans) (Strandvik B et al. Genet Test. 2001;5(3):235-42). Another study report this mutation 67 patients who were compound heterozygous for another CF-causing mutation. These patients predominantly had normal lung function, elevated sweat chloride levels, and pancreatic sufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473295	SCV004213265	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000727627	SCV004226569	pathogenic	not provided	2024-09-16	criteria provided, single submitter	clinical testing	PP3, PM2_moderate
GenomeConnect, ClinGen	RCV000056382	SCV001423365	not provided	Cystic fibrosis		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 10-07-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000727627	SCV001741074	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000727627	SCV001952249	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727627	SCV001968100	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826603	SCV002080124	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826603	SCV002507478	pathogenic	CFTR-related disorder	2019-06-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826603	SCV004739793	pathogenic	CFTR-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The CFTR c.349C>T variant is predicted to result in the amino acid substitution p.Arg117Cys. This variant has previously been reported to be causative for cystic fibrosis and CFTR-related disorders (Dörk et al. 1994. PubMed ID: 7525450; Steiner et al. 2011. PubMed ID: 21520337; Sosnay et al. 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399; www.cftr2.org). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.