ClinVar

Description

Variant summary: CFTR c.1052C>G (p.Thr351Ser) results in a conservative amino acid change in 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 0.00019 in 251742 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00019 vs 0.013), allowing no conclusion about variant significance. c.1052C>G has been reported in the literature in individuals affected with Cystic Fibrosis, CBAVD, chronic pancreatitis and diffuse bronchiectasis, without strong evidence of causality (Mercier_1993, Dork_1997, Schrijver_2005, Bienvenu_2010, de Cid_2010, Dal Maso_2013, Masson_2013, Trujillano_2013, Grangeia_2018, Rispoli_2020, da Silva Filho_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. At-least two co-occurrences in cis with other pathogenic variants have been reported (e.g. CFTR c.3484C>T, p.Arg1162X; CFTR c.1521_1523del, p.Phe508del) (Mercier_1993, Dal Maso_2013), providing supporting evidence for a benign role. One of these reports was in an obligate carrier father of an individual with CF (in cis with p.Arg1162X, Mercier_1993) while the other was in an individual reportedly affected with CF who harbored a non-informative genotype attributed to a synonymous variant (p.Pro1290=) in trans (in cis with p.Phe508del, Del Maso_2013). At least two publications report experimental evidence evaluating an impact on protein function (Bergougnoux_2023, Bihler_2024). The variant did not show any deleterious impact on mRNA or protein expression and Western blot results were not suggestive of a folding defect. However, the most pronounced variant effect resulted in approximately 46% 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: 20167849, 33572515, 23670503, 20059485, 9272157, 18716917, 29589582, 16128988, 23951356, 8477260, 25735457, 32185651, 15858154, 23687349, 32819855, 19812525, 36567205, 38388235). ClinVar contains an entry for this variant (Variation ID: 53174). Based on the evidence outlined above, the variant was classified as uncertain significance.