Submissions for variant NM_000492.4(CFTR):c.1753G>T (p.Glu585Ter)

gnomAD frequency: 0.00001  dbSNP: rs397508296

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056353	SCV000071534	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000056353	SCV000220495	pathogenic	Cystic fibrosis	2014-07-09	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000724156	SCV000331671	pathogenic	not provided	2017-08-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000056353	SCV000886253	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781242	SCV000919148	pathogenic	not specified	2017-10-12	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1753G>T (p.Glu585X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/244858 control chromosomes at a frequency of 0.0000204 (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant of interest has been reported in multiple affected individuals (Sosnay 2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV001004271	SCV001163147	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056353	SCV001169428	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000724156	SCV001449645	pathogenic	not provided	2016-04-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056353	SCV001579160	pathogenic	Cystic fibrosis	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu585*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs397508296, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis or chronic pancreatitis (PMID: 1284538, 15480987, 23974870, 25492507, 25910067). ClinVar contains an entry for this variant (Variation ID: 53374). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724156	SCV001714836	pathogenic	not provided	2020-12-11	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3, PP5
Arcensus	RCV000056353	SCV002564617	pathogenic	Cystic fibrosis	2013-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056353	SCV002716154	pathogenic	Cystic fibrosis	2022-06-23	criteria provided, single submitter	clinical testing	The p.E585* pathogenic mutation (also known as c.1753G>T), located in coding exon 13 of the CFTR gene, results from a G to T substitution at nucleotide position 1753. This changes the amino acid from a glutamic acid to a stop codon within coding exon 13. In one study, this nonsense mutation was found in four unrelated cystic fibrosis patients (Cremonesi L et al. Hum. Mutat., 1992;1:314-9). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056353	SCV003921078	pathogenic	Cystic fibrosis	2023-03-02	criteria provided, single submitter	clinical testing	Criteria applied: PVS1, PM3_STR, PM2_SUP
Baylor Genetics	RCV003473466	SCV004213392	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031493	SCV005673336	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000056353	SCV005877017	pathogenic	Cystic fibrosis	2024-07-09	criteria provided, single submitter	clinical testing	The CFTR c.1753G>T; p.Glu585Ter variant (rs397508296) is reported in multiple cystic fibrosis patients and is commonly associated with pancreatic insufficiency (CFTR2 database, Cremonesi 1992, Hirtz 2004, Ooi 2012, Sosnay 2013). This variant is also reported in ClinVar (Variation ID: 53374). It is only observed on five alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ 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. 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. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. PMID: 22658665. 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.
Natera, Inc.	RCV001831737	SCV002080668	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001831737	SCV005348216	pathogenic	CFTR-related disorder	2024-05-08	no assertion criteria provided	clinical testing	The CFTR c.1753G>T variant is predicted to result in premature protein termination (p.Glu585*). This variant has been reported to be causative for cystic fibrosis (Cremonesi et al. 1992. PubMed ID: 1284538; Sosnay et al. 2013, PubMed ID: 23974870). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.