ClinVar Genomic variation as it relates to human health

Variant summary: CFTR c.1116+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 5/5 computational tools predict the variant abolishes a 5 splicing donor site and a 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 4e-06 in 250560 control chromosomes (gnomAD). The variant, c.1116+1G>A, has been reported in the literature in multiple individuals affected with Cystic Fibrosis or CBAVD (Kambouris_2000, Huber_2002, Kammesheidt_2006, Steiner_2011, Qiu_2018, Petrova_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The c.1116+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide(s) after coding exon 8 of the CFTR gene. This alteration was identified in an individual with cystic fibrosis; however a second CFTR variant was not detected (Kambouris M et al. Eur. J. Pediatr., 2000 May;159:303-9). It was also identified in a cohort of individuals with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with a second CFTR variant; however, the phase was not provided (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). This alteration is also associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Of note, this alteration is also known as 1248+1G>A in published literature. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation.

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

This sequence change affects a donor splice site in intron 8 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs397508158, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 10834512, 15365999, 21520337, 23974870, 30548586). This variant is also known as c.1248+1G>A. ClinVar contains an entry for this variant (Variation ID: 53190). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.