ClinVar

Description

Variant summary: CFTR c.358G>A (p.Ala120Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 6.7e-05 in 1618662 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (6.7e-05 vs 0.013), allowing no conclusion about variant significance. The c.358G>A variant has been reported in the literature in heterozygous or presumed compound heterozygous state in several individuals affected with Non-Classic Cystic Fibrosis (example, Chillon_1994, Kanavakis_2003, Radivojevic_2004), as well as CBAVD, asthma, ICP, and lung disease patients, though full genotype information and sweat test results were often not reported or normal, making interpretation difficult. A few studies reported the variant in compound heterozygosity with a known pathogenic variant (p.F508del) in individuals with intermediate or abnormal sweat chloride test values, with at least one of them affected with pancreatic insufficiency and another one affected with recurrent pneumonia (example, De Wachter_2017, Sasihuiseyinoglu_2019, Munck_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 46.73% of normal chloride channel conductance relative to wild type (example, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 31488014, 21198395, 9439669, 7513293, 7517264, 28830496, 9272157, 15537723, 12752573, 10439967, 23951356, 31916691, 11883825, 15727251, 22427236, 31990467, 21520337, 17489851, 11354633, 38388235). ClinVar contains an entry for this variant (Variation ID: 53774). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.