ClinVar

Description

Variant summary: CFTR c.3469-17T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00059 in 250506 control chromosomes, predominantly at a frequency of 0.0033 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00059 vs 0.013), allowing no conclusion about variant significance. c.3469-17T>C has been reported in the literature as non-informative genotypes (second allele and/or phase not specified) in cohorts of individuals affected with Cystic Fibrosis, diffuse bronchiectasis and azoospermia (e.g. Audrezet_1993, Claustres_2000, Scotet_2003, Gallati_2009, Soltysova_2018, Vaidyanathan_2022) but it was also reported in healthy controls (e.g. Bergougnoux_2015). These report(s) do not provide unequivocal conclusions about a penetrant association of the variant with fulminant Cystic Fibrosis. The variant was found to co-occur with two other deleterious CFTR variants (c.1393-1G>A and c.5T_TG12) in at-least one specimen tested at our laboratory. The phase of this variant was not determined, however it provides supporting evidence for a benign role. 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: 7683952, 25797027, 10923036, 18685558, 20021716, 28456595, 26847993, 17890437, 12815607, 28544683, 35857025, 23503723). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=2), likely benign (n=1), or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign.