ClinVar Genomic variation as it relates to human health

The c.273+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the CFTR gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/250546) total alleles studied. The highest observed frequency was 0.001% (1/113238) of European (non-Finnish) alleles. This variant, also known as c.405+1G>A in published literature, has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 07/25/2022). This nucleotide position is highly conserved in available vertebrate species. Functional in vitro studies found that cells carrying this pathogenic mutation had elevated sweat chloride levels and decreased lung function (Sosnay, 2013). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

NM_000492.3(CFTR):c.273+1G>A(aka 405+1G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.273+1G>A(aka 405+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã

Variant summary: Variant summary: The CFTR c.273+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict significant impact on normal splicing. These predictions were confirmed by a functional study, where authors showed that this change eliminated canonical donor site and lead to exon skipping in epithelial CFTR mRNA, subsequently introducing a frameshift with premature stop codon (Drk_1993). This variant was found in 1/245276 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant of interest has been reported in multiple affected individuals presented with classical CF (Sosnay_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The variant is located in a canonical splice-donor site and interferes with normal CFTR mRNA splicing. The variant has been reported in individuals affected with cystic fibrosis in the published literature (PMID: 22975760 (2013), 23974870 (2013), 15948195 (2005), 11336401 (2001), 7506605 (1993)). The variant has been shown to result in a frameshift resulting in premature termination of protein synthesis (PMID: 7506605 (1993)). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic.

This sequence change affects a donor splice site in intron 3 of the CFTR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs121908791, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 7506605, 23974870, 28546993). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 405+1G>A. ClinVar contains an entry for this variant (Variation ID: 53549). Studies have shown that disruption of this splice site results in skipping of exon 3 and introduces a premature termination codon (PMID: 7506605). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.