Submissions for variant NM_000492.4(CFTR):c.1680-1G>A

gnomAD frequency: 0.00001  dbSNP: rs121908794

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056352	SCV000071453	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Mendelics	RCV000056352	SCV000886192	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985679	SCV001134121	pathogenic	not provided	2018-12-14	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. Occurs in multiple cases with a recessive pathogenic variant in the same gene.
Baylor Genetics	RCV001004264	SCV001163140	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056352	SCV001169391	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000056352	SCV001194022	pathogenic	Cystic fibrosis	2019-12-09	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1680-1G>A(aka 1812-1G>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 10077727, 17331079, 11388756, 7517264, 18456578, 23974870 and 16963320. Classification of NM_000492.3(CFTR):c.1680-1G>A(aka 1812-1G>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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056352	SCV001442669	pathogenic	Cystic fibrosis	2020-10-01	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1680-1G>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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3 acceptor site. Four predict the variant creates a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250274 control chromosomes (gnomAD). c.1680-1G>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Chillon_1994, Watson_2004, Sosnay_2013). 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. Five ClinVar submitters, including one expert panel (CFTR2), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000056352	SCV001469024	pathogenic	Cystic fibrosis	2020-12-22	criteria provided, single submitter	clinical testing
Invitae	RCV000056352	SCV001586673	pathogenic	Cystic fibrosis	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 12 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 (rs121908794, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 7517264, 16786510, 23974870, 25667564, 25674778, 27086061). This variant is also known as 1812-1G>A. ClinVar contains an entry for this variant (Variation ID: 48681). 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000056352	SCV002507359	pathogenic	Cystic fibrosis	2020-07-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056352	SCV002714500	pathogenic	Cystic fibrosis	2018-11-09	criteria provided, single submitter	clinical testing	The c.1680-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 13 of the CFTR gene. This mutation was first reported in a Spanish cystic fibrosis cohort (Chillón M, Hum. Mutat. 1994; 3(3):223-30) and is associated with elevated sweat chloride levels, decreased lung function, pancreatic insufficiency, and Pseudomonas infection (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 21, 2015). In addition, this alteration has been detected in several cohort of individuals with diagnoses or suspected diagnoses of CF (Schrijver I et al. J Mol Diagn, 2016 Jan;18:39-50). (Felício V et al. Clin. Genet., 2017 03;91:476-481). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000056352	SCV003807339	pathogenic	Cystic fibrosis	2022-09-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 moderated
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000056352	SCV004176682	pathogenic	Cystic fibrosis	2023-03-01	criteria provided, single submitter	clinical testing	The invariant splice acceptor c.1680-1G>A in CFTR gene has been reported in compound heterozygous state in multiple individuals affected with Cystic Fibrosis (Felício V et al. 2017; Gaitch N et al. 2016; Schrijver I et al. 2016). The c.1680-1G>A variant has allele frequency 0.0004% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submiters). loss-of-function variants in CFTR are known to be pathogenic (Chillón M et al. 1994). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473293	SCV004213394	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826602	SCV002080647	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826602	SCV002507443	pathogenic	CFTR-related disorders	2020-07-28	no assertion criteria provided	clinical testing