ClinVar

Description

Variant summary: CFTR c.2042A>T (p.Glu681Val) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) 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 0.00014 in 249118 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. c.2042A>T has been reported in the literature in individuals affected with Nontuberculous mycobacteria (NTM) infection, pancreatitits and CBAVD (Congenital bilateral absence of the vas deferens) (example, Colombo_2009, Jang_2013, Xiao_2017, Yuan_2019, Guan_2018). These reports however, 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: 19858235, 29997923, 23514810, 29173301, 30811104). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one as likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.