ClinVar Genomic variation as it relates to human health

The CFTR c.3158C>T; p.Thr1053Ile variant (rs140883683) has been reported in individuals affected with atypical cystic fibrosis (such as congenital absence of vas deferens), in-trans with the p.Phe508del variant (Groman 2002, SickKids CFTR database). It has also been reported in-cis with the 5T allele in multiple individuals (Claustres 2000, Groman 2002, SickKids CFTR database), and not causative of classic cystic fibrosis when found in-trans with a severe pathogenic CFTR variant (Sobczynska-Tomaszewska 2013). The variant is listed in ClinVar (Variation ID: 53666), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at residue 1053 is moderately conserved, and computational algorithms predict that this variant is deleterious (REVEL: 0.899). While available information suggests this variant may be part of a complex variant with the 5T allele, it is uncertain whether this is always the case. Therefore, the clinical significance of the p.Thr1053Ile variant is uncertain at this time. References: Link to SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=977 Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000; 16(2):143-56. PMID: 10923036. Groman J et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002; 347(6):401-7. PMID: 12167682. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046. Sobczynsk-Tomaszewska A et al. Newborn screening for cystic fibrosis: Polish 4 years' experience with CFTR sequencing strategy. Eur J Hum Genet. 2013; 21(4):391-6. PMID: 22892530.

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1053 of the CFTR protein (p.Thr1053Ile). This variant is present in population databases (rs140883683, gnomAD 0.002%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic CFTR variant in two individuals who were not confirmed to have cystic fibrosis (CF) (PMID: 22892530). It was also found in individuals affected with nonclassic CF and congenital bilateral absence of the vas deferens (CBAVD), but further analysis revealed that the c.3158C>T missense substitution was on the same chromosome as the pathogenic 5T allele in both patients (PMID: 12167682, 10923036). These findings suggest that this missense variant was not a contributory cause of disease in these patients. ClinVar contains an entry for this variant (Variation ID: 53666). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). 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.T1053I variant (also known as c.3158C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3158. The threonine at codon 1053 is replaced by isoleucine, an amino acid with similar properties. This variant was reportedly identified in cis with the 5T allele in a male with congenital bilateral absence of the vas deferens (Claustres M et al. Hum. Mutat., 2000;16:143-56) and it has also been described in an individual heterozygous for p.F508del and the 5T allele, phase unknown, presenting with nonclassic cystic fibrosis (Groman JD et al. N. Engl. J. Med., 2002 Aug;347:401-7). In another study, this variant was observed in conjunction with p.F508del in two unrelated newborns who had positive immunoreactive trypsin screening; the phase of these CFTR alterations is unknown and further clinical evaluation determined they were not affected with classic cystic fibrosis (Sobczyska-Tomaszewska A et al. Eur. J. Hum. Genet., 2013 Apr;21:391-6). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.

Variant summary: CFTR c.3158C>T (p.Thr1053Ile) 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 8e-06 in 250422 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3158C>T has been reported in the literature in individuals, predominantly found to co-occur in cis with the 5T allele, along with two newborns (no CF detected) that carry the variant in trans with deltaF508 (Claustres_2000, Groman_2002, Sobczynska-Tomaszewska_2013). However, it is unclear whether the variant is a considered a complex allele with 5T. These reports do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk. At least two functional study reports experimental evidence evaluating an impact on protein function (Raraigh_2018, Bihler_2024). The most pronounced variant effect resulted in approximately (Gt channel conductance) 85% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 11504857, 10923036, 20059485, 12167682, 25735457, 29805046, 26708955, 22892530, 38388235). ClinVar contains an entry for this variant (Variation ID: 53666). Based on the evidence outlined above, the variant was classified as uncertain significance.