ClinVar Genomic variation as it relates to human health

The CFTR c.3181G>C, p.Gly1061Arg variant has been reported in cystic fibrosis patients (Alper 2004, Mercier 1993, Visich 2002, SickKids CFTR database, CFTR2 database), with variable presentation of pancreatic insufficiency (CFTR2 database). Functional characterization of the variant protein indicates that chloride conductance is severely impaired (CFTR2 database). The variant is listed in the ClinVar database (Variation ID: 53672), in the dbSNP variant database (rs142394380), and observed in the general population databases at a frequency of 0.02 percent in the 1000 Genomes Project, and 0.0077 percent in the Exome Variant Server. The glycine at residue 1061 is highly conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as moderately pathogenic. References: CFTR2 database: https://cftr2.org/ Link to p.Gly1061Arg in SickKids database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=443 Alper OM et al. Identification of novel and rare mutations in California Hispanic and African American cystic fibrosis patients. Hum Mutat. 2004 Oct;24(4):353. Mercier B et al. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene. Genomics. 1993 16(1):296-7. Visich A et al. Complete screening of the CFTR gene in Argentine cystic fibrosis patients. Clin Genet. 2002 Mar;61(3):207-13.

This missense change has been observed in individuals with cystic fibrosis (PMID: 7683628, 8723695, 9084934; The Clinical and Functional TRanslation of CFTR (CFTR2) at http://cftr2.org). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1061 of the CFTR protein (p.Gly1061Arg). ClinVar contains an entry for this variant (Variation ID: 53672). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive.

Variant summary: CFTR c.3181G>C (p.Gly1061Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250828 control chromosomes (gnomAD). c.3181G>C has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Alper_2004, Bienvenu_1995, Chertkoff_1997, Mercier_1993). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to cause misprocessing and failure of maturation of CFTR resulting in its retention in the endoplasmic reticulum (Seibert_1996). Three ClinVar submitters including an expert panel (CFTR2) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.G1061R pathogenic mutation (also known as c.3181G>C and c.3313G>C), located in coding exon 20 of the CFTR gene, results from a G to C substitution at nucleotide position 3181. The glycine at codon 1061 is replaced by arginine, an amino acid with dissimilar properties. This variant has been confirmed in trans and identified likely in trans with a CFTR pathogenic variant in multiple individuals with clinical features of cystic fibrosis and CFTR-related disorders including, but not limited to: elevated sweat chloride levels, pulmonary disease, and pancreatic insufficiency (Bienvenu T et al. Hum Mutat, 1996;7:376-7; Mercier B et al. Genomics, 1993 Apr;16:296-7; Ravnik-Glavac M et al. Hum Mutat, 2002 Apr;19:374-83; Sala MA et al. J Cyst Fibros, 2021 Mar;20:356-363; Ambry internal data). In one functional study, this mutation was observed to result in protein misprocessing and failure of protein maturation (Seibert FS et al. J Biol Chem. 1996;271(25):15139-45). This variant is considered to be rare based on population 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.