ClinVar Genomic variation as it relates to human health

NM_000492.3(CFTR):c.1438G>T(G480C) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 11388756, 11823443, 1376016, 7757078 and 16132229. Classification of NM_000492.3(CFTR):c.1438G>T(G480C) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.

Variant summary: CFTR c.1438G>T (p.Gly480Cys) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251304 control chromosomes. c.1438G>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Kristidis_1992, Petrova_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence and showed that this variant affects CFTR function (e.g. Smit_1995, Dickinson_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.G480C pathogenic mutation (also known as c.1438G>T), located in coding exon 11 of the CFTR gene, results from a G to T substitution at nucleotide position 1438. The glycine at codon 480 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported in individuals with cystic fibrosis (Tsui LC. Hum. Mutat., 1992;1:197-203; Smit LS Hum. Mol. Genet. 1995 Feb;4(2):269-73) and was shown to be associated with severe pancreatic insufficiency (Kristidis P et al. Am. J. Hum. Genet., 1992 Jun;50:1178-84). Functional studies suggested that this mutation impacts CFTR protein trafficking (Smit LS et al. Hum. Mol. Genet., 1995 Feb;4:269-73; Dickinson P et al. Hum. Mol. Genet., 2002 Feb;11:243-51). Based on the available evidence, the p.G480C is classified as a pathogenic mutation.

This CFTR variant previously been identified in multiple individuals with a clinical presentation consistent with cystic fibrosis and is reported in ClinVar as pathogenic or likely pathogenic by two laboratories. Additionally, functional analysis support the deleterious effect of this missense change, located in the first nucleotide binding domain of the protein, on CFTR trafficking. This CFTR variant (rs79282516) is rare (<0.1%) in one large population dataset6 and absent from another (gnomAD: 1/31382 total alleles; 0.003187%; no homozygotes). We consider this variant to be pathogenic.

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: PS3_SUP, PM2_SUP, PM3_STR, PM5_STR, PP3

This variant is present in population databases (rs79282516, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 480 of the CFTR protein (p.Gly480Cys). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1376016, 7757078, 9150159, 26708955). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 7757078, 11823443, 27340661). 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. ClinVar contains an entry for this variant (Variation ID: 7187).