ClinVar

Description

Variant summary: CFTR c.2417A>G (p.Asp806Gly) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 1.1e-05 in 179966 control chromosomes.c.2417A>G has been observed in the compound heterozygous state in individuals affected with cystic fibrosis (Strom_2003, Petrova_2019), however, it was also observed in trans with a pathogenic variant (p.F508del) in a newborn with a negative sweat test (Narzi_2007). In addition, the variant was listed to be found in cohorts of CF patients and newborns with positive screening tests, however no second variant was specified in these cases (Atag_2019, PIcci_2010, Bozdogan_2021). These data do not allow clear conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant resulted in approximately 50% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 30938940, 38388235, 33572515, 25880441, 34405919, 17594398, 30548586, 19897426, 25735457, 12544470, 36717774). ClinVar contains an entry for this variant (Variation ID: 53487). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.