ClinVar Genomic variation as it relates to human health

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1057 of the CFTR protein (p.Thr1057Ala). This variant is present in population databases (rs397508511, gnomAD 0.01%). This missense change has been observed in individual(s) with mild clinical features of cystic fibrosis (PMID: 23670503, 32819855). ClinVar contains an entry for this variant (Variation ID: 53668). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.T1057A variant (also known as c.3169A>G), located in coding exon 20 of the CFTR gene, results from an A to G substitution at nucleotide position 3169. The threonine at codon 1057 is replaced by alanine, an amino acid with similar properties. This variant was reported in an individual with suspected mild or atypical cystic fibrosis; no second variant was detected in the individual and clinical information was not provided (Dal'Maso VB et al, J Bras Pneumol; 39(2):181-9). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Variant summary: CFTR c.3169A>G (p.Thr1057Ala) 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 3.2e-05 in 250640 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3169A>G has been reported in the literature in individuals affected with Cystic Fibrosis (DalMaso_2013, Rispoli_2020, da Silva_2020, Bozdogan_2021). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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: 16311287, 11504857, 23670503, 25735457, 32819855, 32185651, 33572515). ClinVar contains an entry for this variant (Variation ID: 53668). Based on the evidence outlined above, the variant was classified as uncertain significance.