ClinVar Genomic variation as it relates to human health

Also known as c.3601-17T>C, observed in individuals with cystic fibrosis, but additional information was not provided (Audrezet et al., 1993; Soltysova et al., 2018); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 26847993, 28456595, 20021716, 10439967, 17890437, 18685558, 23503723, 25797027, 28544683, 10923036, 12815607, 34426522, 7683952)

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.

The CFTR c.3469-17T>C variant has been reported in the published literature in individuals with cystic fibrosis (PMID: 7683952 (1993), 12815607 (2003), 28544683 (2017)) and CFTR-RD, including azoospermia (PMID: 20021716 (2009), 28456595 (2017)) as well as in unaffected individuals (PMID: 17890437 (2007)). The frequency of this variant in the general population, 0.0033 (100/30538 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CFTR mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.