ClinVar

Description

Variant summary: CFTR c.743G>C (p.Arg248Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251316 control chromosomes (gnomAD). c.743G>C has been reported in the literature in individuals affected with CFTR-Related Diseases, including an adult man diagnosed with azoospermia/male infertility (e.g. Oud_2017) and one young man diagnosed with CFTR-RD hepatopathy with elevated sweat chloride concentrations (e.g. Polizzi_2011). These data indicate that the variant may be associated with disease. 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: 21931512, 28801929). ClinVar contains an entry for this variant (Variation ID: 54053). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.