PP3, PM2_supporting, PM3_supporting

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 866 of the CFTR protein (p.Cys866Tyr). This variant is present in population databases (rs193922506, gnomAD 0.02%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 1284534, 10923036, 11379874). ClinVar contains an entry for this variant (Variation ID: 35843). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. 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.C866Y variant (also known as c.2597G>A), located in coding exon 15 of the CFTR gene, results from a G to A substitution at nucleotide position 2597. The cysteine at codon 866 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been described in a patient with echogenic bowel, but no other symptoms were reported (Ferec et al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids; 1991; Tsui LC. Hum. Mutat., 1992;1:197-203). In addition, this alteration has been detected in individuals with nonspecific heart and lung phenotypes via whole exome sequencing and in individuals with cystic fibrosis; however, no specific clinical details were provided (Tabor HK et al. Am. J. Hum. Genet., 2014 Aug;95:183-93; Salvatore F et al. Am. J. Med. Genet., 2002 Jul;111:88-95; Ravnik-Glavac M et al. Hum. Mol. Genet., 1994 May;3:801-7; Claustres M et al. Hum. Mutat., 2000;16:143-56; Amorim CEG et al. PLoS Genet., 2017 Sep;13:e1006915). In an assay testing CFTR function, this variant showed a functionally abnormal result (Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Variant summary: CFTR c.2597G>A (p.Cys866Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4.8e-05 in 251302 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.2597G>A has been reported in the literature in 1 homozygous individual with Cystic Fibrosis without detailed clinical presentations (Baaran_2021) and in at least one individual affected with Cystic Fibrosis without a reported second variant (Tsui_1992, Le Marechal_2001). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately (Gt channel conductance) 13% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 12124743, 7521710, 10923036, 1284534, 8844213, 11379874, 19139070, 25087612, 25735457, 34996830, 35110256). ClinVar contains an entry for this variant (Variation ID: 35843). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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