ClinVar Genomic variation as it relates to human health

Variant summary: The CFTR c.1766+5G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 4/5 splicing algorithms predict the weakening or elimination of the splice donor site of exon 13. This prediction is confirmed by cDNA studies performed on RNA isolated from a homozygous patient, showing >95% of transcripts lacking exon 13. This variant was found in 2/119622 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). c.1766+5G>T has been cited in numerous CF patients reported in the literature in both compound heterozygous and homozygous states. Taken together, this variant is classified as Pathogenic.

The c.1766+5G>T (NM_000492.3 c.1766+5G>T) variant in CFTR has been reported in 1 homozygous and 3 compound heterozygous Asian individuals with clinical features of cystic fibrosis (Zielenski 1995, Leung 2016, Shen 2016). This variant has be en identified in 0.023% (2/8,562) of East Asian chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121908796). This variant is located in the 3' splice region. Computational tools suggest a possib le impact to splicing consistent with the +5 position being predominantly a G nu cleotide. In summary, the clinical significance of the c.1766+5G>T variant is li kely pathogenic based upon biallelic case observations, suggestive splicing impa ct and low frequency in the general population.

The CFTR c.1766+5G>T variant is predicted to interfere with splicing. This variant, also referred to as c.1898+5G>A using legacy nomenclature, has been reported in the homozygous and compound heterozygous state in patients with cystic fibrosis (Zielenski et al 1995. PubMed ID: 7543385; Castellani C et al 2008. PubMed ID: 18456578; Shen Y et al 2020. PubMed ID: 32761997 ). Another substitution at this same nucleotide position, c.1766+5G>A, has also been reported as causative for cystic fibrosis (des Georges et al 2004. PubMed ID: 15698946; Raynal C et al 2013. PubMed ID: 23381846). Both variants have been reported to result in exon 12 skipping due to alteration of splicing at the exon 12/intron 12 boundary region (Zielenski et al 1995. PubMed ID: 7543385; Raynal C et al 2013. PubMed ID: 23381846). This variant is reported in 0.040% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117230498-G-T). This variant is interpreted as pathogenic.

This sequence change falls in intron 13 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs121908796, gnomAD 0.04%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 7543385, 10925568, 12874665, 18456578). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of East Asian ancestry (PMID: 18456578). This variant is also known as c.1898+5G>T. ClinVar contains an entry for this variant (Variation ID: 48685). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 7543385, 23381846). For these reasons, this variant has been classified as Pathogenic.

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

NM_000492.3(CFTR):c.1766+5G>T(aka 1898+5G>T) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 23089694, 8213163, 25580864, 16202790, 7543385, 23381846, 12874665 and 18456578. Classification of NM_000492.3(CFTR):c.1766+5G>T(aka 1898+5G>T) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

The CFTR c.1766+5G>T variant (rs121908796), also known as 1898+5G>T, is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with cystic fibrosis, and is a common variant in East Asian patients (Chen 2012, Liu 2015, Shen 2016, Sontag 2005, Xu 2017). This variant is reported in ClinVar (Variation ID: 48685), and is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. In vitro functional assays show that this variant results in skipping of exon 12 (Raynal 2013). Based on available information, this variant is considered to be pathogenic. References: Chen CH et al. Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis. J Formos Med Assoc. 2012;111(10):580-583. PMID: 23089694. Liu Y et al. Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients. Respirology. 2015;20(2):312-318. PMID: 25580864. Raynal C et al. A classification model relative to splicing for variants of unknown clinical significance: application to the CFTR gene. Hum Mutat. 2013;34(5):774-784. PMID: 23381846. Shen Y et al. Clinical Phenotypes and Genotypic Spectrum of Cystic Fibrosis in Chinese Children. J Pediatr. 2016;171:269-76.e1. PMID: 26826884. Sontag MK et al. Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes. J Pediatr. 2005;147(3 Suppl):S83-S88. PMID: 16202790. Xu J et al. Four case reports of Chinese cystic fibrosis patients and literature review. Pediatr Pulmonol. 2017;52(8):1020-1028. PMID: 28608624.

The c.1766+5G>T intronic pathogenic mutation results from a G to T substitution 5 nucleotides after coding exon 13 in the CFTR gene. This mutation is also known as c.1898+5G>T in published literature. One study identified a CF patient with high sweat levels, respiratory complications and pancreatic insufficiency who carried this mutation in trans with a complex allele (Alper OM et al J Formos Med Assoc. 2003;102(5):287-291). One CF review article indicates that this mutation might account for almost 30% of carrier alleles in the Chinese/Taiwanese population, keeping in mind the small sample sizes (Zielenski et al Annu Rev Genet. 1995; 29:777-807). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native donor splice site. In-vitro functional studies indicate an alternate transcript is formed 77-80% of the time due to exon skipping and an in-frame deletion of exon 12 (Raynal et al Hum Mutat 2013; 34(5):774-784). Based on the supporting evidence, c.1766+5G>T is interpreted as a disease-causing mutation.