Submissions for variant NM_000492.4(CFTR):c.274-1G>A

gnomAD frequency: 0.00002  dbSNP: rs121908792

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056370	SCV000071460	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000224434	SCV000230105	pathogenic	not provided	2014-06-24	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224434	SCV000281344	pathogenic	not provided	2015-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056370	SCV000696918	pathogenic	Cystic fibrosis	2017-04-24	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.274-1G>A variant (alternatively also known as 406-1G>A) involves the alteration of a highly conserved nucleotide in the consensus splice acceptor site in intron 3, therefore it is expected to cause aberrant splicing. 5/5 splice prediction tools also predict the abrogation of the splice acceptor site. Thus this variant is very likely to result in loss of function which is a known disease mechanism in CF. This variant was found in 1/116316 control chromosomes from ExAC at a frequency of 0.0000086, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant is found in several CF patients, mainly in Hispanic CF population in compound heterozygous state with other likely or known pathogenic variants. In a large CF population from North American and Europe, its allele frequency was found to be at 0.03% (Sosnay_2013). Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224434	SCV000889297	pathogenic	not provided	2017-10-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763148	SCV000893735	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004422	SCV001163466	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000056370	SCV001193957	pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.274-1G>A(aka 406-1G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 21416780, 17331079, 11668613, 23974870 and 10798368. Classification of NM_000492.3(CFTR):c.274-1G>A(aka 406-1G>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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056370	SCV001578210	pathogenic	Cystic fibrosis	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 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 (rs121908792, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 10798368, 11668613, 15365999, 23974870, 26708955). This variant is also known as c.406-1G>A. ClinVar contains an entry for this variant (Variation ID: 48680). 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.
Ambry Genetics	RCV000056370	SCV002747515	pathogenic	Cystic fibrosis	2022-08-03	criteria provided, single submitter	clinical testing	The c.274-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 4 of the CFTR gene. This mutation has been reported in multiple cystic fibrosis (CF) patients with a second mutation confirmed in trans; it is associated with elevated sweat chloride levels, pancreatic insufficiency, and Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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.
Baylor Genetics	RCV003473292	SCV004213552	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831712	SCV002080110	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing