ClinVar

Description

Variant summary: CFTR c.1453A>T (p.Ser485Cys) 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 5.6e-05 in 251344 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (5.6e-05 vs 0.013), allowing no conclusion about variant significance. c.1453A>T has been reported in the literature in affected individuals of East Asian ethnicity, predominantly in individuals affected with CBAVD (e.g., Li_2012, Lu_2013, Lu_2014, Luo_2021), but also in individuals with bronchiectasis (e.g., Schrijver_2008; SickKids database) and nontuberculous mycobacteria lung disease (e.g., Jang_2013). However, there was not strong evidence for causality in any of these cases (e.g., lack of co-segregation and co-occurence data as well as uninformative genotypes). These reports therefore do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23514810, 22483971, 24559724, 23953609, 32777524, 35313924, 18556774). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 , and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.