ClinVar

Description

Variant summary: CFTR c.3322G>C (p.Val1108Leu) results in a 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 1.6e-05 in 250936 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3322G>C has been reported in the literature as a non-informative genotype (second allele not-specified) or in cis with a pathogenic CFTR allele (see detailed below) in individuals with features of CBAVD, chronic bronchitis (COPDGene study cohort) (example, Grangeia_2007, Steiner_2011, Pagin_2016, Safareli_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At-least one co-occurrence in cis with another pathogenic variant(s) have been reported (CFTR c.3454G>C, p.Asp1152His) reportedly in trans with the 5T allele in an individual with CBAVD, providing supporting evidence for a benign role (Steiner_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.