ClinVar Genomic variation as it relates to human health

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11278813, 19236881, 7689013, 26500004, 16049310, 20932301, 11180668, 9452048, 20706124, 10923036)

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 11278813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 53764). This variant is also known as 482G>C. This missense change has been observed in individuals with clinical features of cystic fibrosis (PMID: 7689013, 9401110, 9452048, 26500004; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 117 of the CFTR protein (p.Arg117Pro).

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM1, PM2_SUP, PM3_STR, PM5_STR, PP3, PP4

The p.R117P variant (also known as c.350G>C), located in coding exon 4 of the CFTR gene, results from a G to C substitution at nucleotide position 350. The arginine at codon 117 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected as both heterozygous and compound heterozygous in several individuals with cystic fibrosis (CF) and CFTR-related disorders (Pepermans X et al. Clin. Biochem., 2016 Jan;49:154-60; Reiss J et al. Hum. Mol. Genet., 1993 Jun;2:809-11; Feldmann D et al. Hum. Mutat., 1998;Suppl 1:S78-80; Claustres M et al. Hum. Mutat., 2000;16:143-56). In addition, four different variants located at the same position, p.R117H, p.R117G, p.R117L, and p.R117C, have been reported in individuals with CF and CFTR-related disorders (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7; Dörk T et al. Hum Genet. 1994;94(5):533-42; Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75; Claustres M et al. Hum. Mutat., 2000;16:143-56; Daudin M et al. Fertil. Steril., 2000 Dec;74:1164-74; Thauvin-Robinet C et al. J. Med. Genet., 2013 Apr;50:220-7). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.