Submissions for variant NM_000492.4(CFTR):c.1766+5G>T

gnomAD frequency: 0.00001  dbSNP: rs121908796

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046468	SCV000677595	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046468	SCV000074481	pathogenic	Cystic fibrosis	2024-03-06	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046468	SCV000696872	pathogenic	Cystic fibrosis	2025-03-05	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1766+5G>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Zielenski_1995). The variant allele was found at a frequency of 2.4e-05 in 249042 control chromosomes. c.1766+5G>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g., Zielenski_1005, Alper_2003, Liu_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Zielenski_1995). The following publications have been ascertained in the context of this evaluation (PMID: 12874665, 25580864, 7543385). ClinVar contains an entry for this variant (Variation ID: 48685). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000046468	SCV000712857	likely pathogenic	Cystic fibrosis	2017-02-10	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV001004274	SCV001163150	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046468	SCV001167246	pathogenic	Cystic fibrosis	2019-10-16	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
CFTR-France	RCV000046468	SCV001169435	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000046468	SCV001194057	likely pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000046468	SCV002713363	pathogenic	Cystic fibrosis	2025-02-13	criteria provided, single submitter	clinical testing	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 alteration was identified in an individual with high sweat chloride 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). This alteration might account for almost 30% of carrier alleles in the Chinese/Taiwanese population (Zielenski et al Annu Rev Genet. 1995; 29:777-807). This variant 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 02/13/2025). This variant has <10% of wild type quantity in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/13/2025). Of note, this alteration is also known as c.1898+5G>T in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor 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, this variant is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV004537158	SCV004113310	pathogenic	CFTR-related disorder	2023-09-30	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003473294	SCV004213346	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001528994	SCV004564618	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	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.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795959	SCV005418869	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP4+PS3
Fulgent Genetics, Fulgent Genetics	RCV004795959	SCV005673338	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-02-17	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528994	SCV001741691	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528994	SCV001963710	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528994	SCV001978000	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Urology, First Affiliated Hospital of Nanjing Medical University	RCV000046468	SCV004217836	pathogenic	Cystic fibrosis	2023-12-25	no assertion criteria provided	clinical testing