ClinVar Genomic variation as it relates to human health

This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 10798368, 10923036, 15698946, 16436643, 16963320, 21184098, 30548586; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1649T>C. ClinVar contains an entry for this variant (Variation ID: 53276). 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. This variant disrupts the p.Ile506 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. This variant is present in population databases (rs397508224, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 506 of the CFTR protein (p.Ile506Thr).

The p.I506T variant (also known as c.1517T>C), located in coding exon 11 of the CFTR gene, results from a T to C substitution at nucleotide position 1517. The isoleucine at codon 506 is replaced by threonine, an amino acid with similar properties. This variant was detected in two cystic fibrosis chromosomes in a Mexican population (Orozco L et al. Hum. Genet. 2000; 106:360-5). In addition, one individual of Iranian descent with a classical presentation of cystic fibrosis was found to be homozygous for this variant (Elahi E et al. J Mol Diagn 2006; 8:119-27). This variant has also been further detected with low frequency in various populations of individuals with cystic fibrosis (Girardet A et al. Clin. Genet. 2007; 72:374-7 and Claustres M et al. Hum. Mutat. 2000; 16:143-56). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This variant was identified in 4 unrelated patients 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, PM3, PM5_STR, PM2_SUP, PP3, PP4

Variant summary: CFTR c.1517T>C (p.Ile506Thr) results in a non-conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251270 control chromosomes (gnomAD). The variant c.1517T>C (aka. c.1649T>C) has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Cystic Fibrosis (des Georges_2004, de Becdelievre_2011, Elahi_2006, Petrova_2019, and in the databases of Sickkids, CFTR-France, and UMD). The variant has also been detected in populations of individuals with cystic fibrosis, but without providing genotype details (e.g. Orozco_2000). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15698946, 21184098, 16436643, 30548586, 11484207). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as pathogenic.