ClinVar

Description

Variant summary: CFTR c.3017C>A (p.Ala1006Glu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251148 control chromosomes. c.3017C>A has been reported in the literature in individuals affected with Cystic Fibrosis (example, Ferec_1995, Alonso_2007, McGinniss_2005, Tomaiuolo_2010, Lucarelli_2015). In several ascertainments, we identified a co-occurrence in cis with another pathogenic variant (CFTR 5T-TG11), providing supporting evidence for a benign role. This variant has also been frequently reported in cis with p.Val562Ile and the 5T-TG11 haplotype (example, Alonso_2007, McGinniss_2005, Tomaiuolo_2010, Lucarelli_2015). However, we have not identified conclusive evidence supporting the pathogenicity of p.Val562Ile in isolation, therefore, the clinical outcome of this triple complex of 5T-TG11, p.Ala1006Glu and p.Val562Ile remains uncertain. At-least two publications report experimental evidence evaluating an impact on protein function in isolation. The most pronounced variant effect results in <10% of normal CFTR activity (example, Han_2018, Raraigh_2018). One clinical diagnostic laboratory and the CFTR2 database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The CFTR2 database classifies the variant as classified the variant as pathogenic and the clinical diagnostic laboratory classified the variant as uncertain significance. Overlapping but not identical evidence utilized in the context of this evaluation have been cited by the clinical diagnostic laboratory submitter. Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly pathogenic.