ClinVar

Description

Variant summary: CFTR c.2476G>A (p.Glu826Lys) results in a conservative amino acid change located in the CFTR regulator domain 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 2.6e-05 in 192496 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2476G>A has been reported in the literature in control individuals (Morea 2005, Tzetis 2007), in a CF patient (Prontera 2016), and in a sarcoidosis patient (Bombieri 1998). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At-least one co-occurrence in cis with other pathogenic variant(s) have been reported (CFTR c.5T_TG12; CFTR c.3308T>A, p.I1103K), providing supporting evidence for a benign role (Claustres 2017, CFTR-France database, Prontera_2016). At least two publications report experimental evidence evaluating an impact on protein function. While the variant did not affect the protein maturation, it was reported to result in a slightly lower open channel probability, however single channel conductances were not different from the wild-type (Wei 1998, Vankeerberghen 1998). Six 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.