ClinVar Genomic variation as it relates to human health

CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information.

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 117 of the CFTR protein (p.Arg117Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with CFTR-related disorders (PMID: 20706124, 27738188). This variant is also known as c.482G>T (p.Arg117Leu). ClinVar contains an entry for this variant (Variation ID: 53765). 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 not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 11278813, 30046002). This variant disrupts the p.Arg117 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7525450, 15482777, 21783433, 22658665, 23974870, 24586523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.R117L pathogenic mutation (also known as c.350G>T), located in coding exon 4 of the CFTR gene, results from a G to T substitution at nucleotide position 350. The arginine at codon 117 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 4, 2019). This mutation has been described in trans with a pathogenic mutation in individuals with a range of clinical phenotypes including: congenital bilateral absence of the vas deferens (CBAVD) with increased sweat chloride levels and no other signs of disease, mild cystic fibrosis (CF) with pancreatic sufficiency, and classic CF with pancreatic insufficiency. It has been most commonly reported as part of a complex allele p.[R117L;L997F]. When CFTR gating activity was measured on epithelial nasal cells, activity was measured at 39% of wild-type in an individual homozygous for the complex allele, while it was 19.5% in a patient compound heterozygous for a different pathogenic mutation (Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75; Terlizzi V et al. J. Med. Genet., 2017 Apr;54:224-235). In addition, the disease-causing mutation p.R117H has been described in the same codon. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Variant summary: CFTR c.350G>T (p.Arg117Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250954 control chromosomes (gnomAD). c.350G>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Ferec_1995, Wallace_2003, D'Apice_2004, Raraigh_2022). Several investigators have also reported that this variant is part of a complex allele with CFTR c.2991G>C (p.Leu997Phe) in patients with cystic fibrosis (Lucarelli_2010, Lucarelli_2015, Terlizzi_2016). Clinical evaluation of patients showed that p.Leu997Phe could be associated to CFTR-RD while the p.[Arg117Leu;Leu997Phe] is associated with a mild CF phenotype (Lucarelli_2010). The c.2991G>C variant, however, is found at a much higher frequency in controls (approximately 0.0022 in the gnomAD database). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired chloride channel stability (Hammerle_2001) and impaired CFTR function (Han_2018). These data indicate that the variant in isolation may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15084222, 7541510, 11278813, 30046002, 20706124, 25910067, 12014388, 34782259, 27738188, 12829453). ClinVar contains an entry for this variant (Variation ID: 53765). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The CFTR c.350G>T (p.Arg117Leu) variant has been reported in the published literature in individuals affected with cystic fibrosis (PMIDs: 7541510 (1995), 30509709 (2018), 34782259 (2021), 32483343 (2020) and LOVD (https://databases.lovd.nl/shared/)). It has been described to have varying phenotypes in different individuals from mild CF to CFTR-related diseases (see CFTR2 (https://cftr2.org/), CFTR-France (https://cftr.iurc.montp.inserm.fr/cgi-bin/home.cgi), and PMID: 38203285 (2023)). The variant was also reported in a newborn child who had a positive screen result, but was asymptomatic at 18 months of age (PMID: 12014388 (2002)). This variant having partial function may be consistent with variable clinical presentation. Functional studies have observed the variant to have reduced chloride conductance activity, less than 10% compared to the wild-type, that improved with drug modulators (PMID: 38388235 (2024) and CFTR2 (https://cftr2.org/)). In some affected individuals, this variant is part of a complex allele where it is found on the same chromosome with c.2991G>C (p.Leu997Phe) (PMIDs: 20706124 (2010), 27738188 (2016), 30577776 (2018), 32060344 (2020)), however, may not be as responsive to drug modulators (PMID: 38388235 (2024)). Other missense changes at the p.Arg117 amino acid position have been reported as pathogenic, including the well-characterized p.Arg117His variant. The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is consistent with 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 likely pathogenic.

Variant interpreted as Pathogenic and reported on 06-04-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.