ClinVar Genomic variation as it relates to human health

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.

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.

PP3, PM2

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.

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.

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.

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD

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.

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.

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.