ClinVar

Description

Variant summary: CFTR c.4312C>T (p.Arg1438Trp) results in a non-conservative amino acid change located in the ATP-binding domain (IPR003439) 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 4e-06 in 250892 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4312C>T has been reported in the literature in individuals who also carried another (potentially) pathogenic CFTR variant in trans, who had positive newborn screening, pancreatitis or cystic fibrosis (Schrijver_2005, Leonardi_2013, Vecchio-Pagan_2016), however in all of these individuals the variant was reported in cis (i.e. as a complex allele) with the common disease variant p.F508del. The variant was also reported in a case with recurrent pancreatitis, however, the genotype information was not provided (Amato_2012). These data therefore do not allow any conclusion about variant significance. The most pronounced variant effect resulted in approximately (Gt channel conductance) 61% 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: 22020151, 29271547, 26087173, 31883651, 23883480, 29569753, 15858154, 27917292, 38388235). ClinVar contains an entry for this variant (Variation ID: 53940). Based on the evidence outlined above, the variant was classified as uncertain significance.