ClinVar

Description

Variant summary: CFTR c.266A>G (p.Tyr89Cys) 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 250722 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.266A>G has been reported in the literature as a non-informative genotype (second allele not specified) among individuals with non-classic features of Cystic Fibrosis and in at-least one newborn with features of Cystic Fibrosis (example, Giusti_2007, Padoan_2000, Straniero_2016). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect despite the authors reporting a glycosylation pattern and a subcellular distribution comparable to WT-CFTR suggesting they might reach the plasma membrane. Single channel patch clamp analysis revealed that this variant displayed abnormal gating but authors suggested that additional studies are needed to corroborate these equivocal findings (Gene_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18306312, 17272608, 10790225, 27488443, 26098992). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.