Submissions for variant NM_000492.4(CFTR):c.1766+3A>G

gnomAD frequency: 0.00001  dbSNP: rs397508298

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056354	SCV000071569	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000301070	SCV000331668	pathogenic	not provided	2016-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056354	SCV000696868	pathogenic	Cystic fibrosis	2025-03-05	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1766+3A>G alters a conserved 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: 3 predict the variant weakens a 5' donor site. At least one publication reports experimental evidence confirming that this variant affects mRNA splicing, and causes exon 12 skipping in a mini-gene system (Dujardin_2011). The variant allele was found at a frequency of 2.5e-06 in 1592600 control chromosomes in the gnomAD database (v4.1 dataset). c.1766+3A>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Dujardin_2011, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23974870, 21317048). ClinVar contains an entry for this variant (Variation ID: 53379). Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000056354	SCV000886223	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
CFTR-France	RCV000056354	SCV001169433	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056354	SCV001574185	pathogenic	Cystic fibrosis	2022-06-13	criteria provided, single submitter	clinical testing	This variant has been observed in individuals with cystic fibrosis (PMID: 15480987, 18178635). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CFTR protein in which other variant(s) (p.Asp579Gly) have been determined to be pathogenic (PMID: 7544319, 15463898, 26494713, 27738188, 27812499). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 13, but is expected to preserve the integrity of the reading-frame (PMID: 21317048, 32935393). ClinVar contains an entry for this variant (Variation ID: 53379). This variant is also known as 1898+3A>G. This variant is not present in population databases (gnomAD no frequency). 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000056354	SCV002507337	pathogenic	Cystic fibrosis	2019-09-04	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000056354	SCV002570332	pathogenic	Cystic fibrosis	2022-09-06	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Ambry Genetics	RCV000056354	SCV002710618	pathogenic	Cystic fibrosis	2021-12-30	criteria provided, single submitter	clinical testing	The c.1766+3A>G (also known as 1898+3A>G) intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 13 in the CFTR gene. This mutation has been reported in cystic fibrosis patients from Italy, Spain, and Finland (Cremonesi L, Hum. Mutat. 1992 ; 1(4):314-9; Casals T, Hum. Genet. 1997 Dec; 101(3):365-70; Kinnunen S, J. Cyst. Fibros. 2005 Dec; 4(4):233-7). This mutation results in full exon skipping resulting in zero correctly spliced RNA (Dujardin G, J. Cyst. Fibros. 2011 May; 10(3):212-6) and it is associated with elevated sweat chloride levels, decreased lung function, and pancreatic sufficiency (Sosnay PR, Nat. Genet. 2013 Oct; 45(10):1160-7, Supplementary Table and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed September 28, 2015). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000301070	SCV003799410	pathogenic	not provided	2022-08-12	criteria provided, single submitter	clinical testing	The CFTR c.1766+3A>G variant (rs397508298), also reported as c.1898+3A>G, is reported in the literature as heterozygous and homozygous in individuals affected with cystic fibrosis (Casals 1997, Cremonsei 1992, Hirtz 2004, Stanke 2008, Sosnay 2013). Functional analyses of the variant found it resulted in the skipping of exon 12 (Dujardin 2011, Fernandez Alanis 2012). This variant is reported as pathogenic by an expert panel ClinVar (Variation ID: 53379) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. PMID: 9439669. Cremonesi L et al. Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes. Hum Mutat. 1992;1(4):314-9. PMID: 1284538. Dujardin G et al. Splicing defects in the CFTR gene: minigene analysis of two mutations, 1811+1G>C and 1898+3A>G. J Cyst Fibros. 2011 May;10(3):212-6. PMID: 21317048. Fernandez Alanis E et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum Mol Genet. 2012 Jun 1;21(11):2389-98. PMID: 22362925. Hirtz S et al. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology. 2004 Oct;127(4):1085-95. PMID: 15480987. Stanke F et al. Diversity of the basic defect of homozygous CFTR mutation genotypes in humans. J Med Genet. 2008 Jan;45(1):47-54. PMID: 18178635. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870.
Baylor Genetics	RCV003466901	SCV004215211	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000056354	SCV001132153	pathogenic	Cystic fibrosis	2019-06-27	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002228155	SCV002507421	pathogenic	CFTR-related disorder	2019-09-04	no assertion criteria provided	clinical testing