Submissions for variant NM_000492.4(CFTR):c.1477C>T (p.Gln493Ter)

gnomAD frequency: 0.00001  dbSNP: rs77101217

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007526	SCV000071546	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007526	SCV000696845	pathogenic	Cystic fibrosis	2016-04-14	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a nonsense change involving a conserved nucleotide resulting in a predicted truncated CFTR protein, a known mechanism for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121326 (1/60663), which does not exceed the predicted maximum expected allele frequency for a pathogenic CFTR variant of 1/77. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable clinical laboratories/databases cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000727628	SCV000854904	pathogenic	not provided	2018-08-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000007526	SCV000883566	pathogenic	Cystic fibrosis	2024-11-14	criteria provided, single submitter	clinical testing	The CFTR c.1477C>T; p.Gln493Ter variant (rs77101217) has been reported in cystic fibrosis patients, often associated with pancreatic insufficiency (CFTR2 database, Kerem 1990, Ooi 2012, Sosnay 2013). This variant is also reported in ClinVar (Variation ID: 7107). It is only found on six 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/ Kerem BS et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447-51. PMID: 2236053. 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.
Illumina Laboratory Services, Illumina	RCV000007526	SCV000915201	pathogenic	Cystic fibrosis	2017-08-15	criteria provided, single submitter	clinical testing	The CFTR c.1477C>T (p.Gln493Ter) stop-gained variant has been reported in at least four studies and is found in a total of six affected individuals including four compound heterozygotes, one complex heterozygote, and one presumed heterozygote (Kerem et al. 1990; Kristidis et al. 1992; Feuillet-Fieux et al. 2011; Steiner et al. 2011). Three of the compound heterozygotes have a clinical diagnosis of cystic fibrosis and pancreatic insufficiency and have the p.Phe508del variant as their second variant (Kristidis et al. 1992). Steiner et al. (2011) reported on a compound heterozygote with a diagnosis of congenital bilateral absence of the vas deferens. Feuillet-Fieux et al. (2011) identified a complex heterozygous individual, with a clinical diagnosis of cystic fibrosis based on sweat chloride values who had no other pulmonary or intestinal symptoms, who carried three other variants on the maternal allele and the p.Gln493Ter variant on the paternal allele. The p.Gln493Ter variant was absent from 2456 controls and is reported at a frequency of 0.000047 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the evidence available, the p.Gln493Ter variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV001004456	SCV001163501	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007526	SCV001169485	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007526	SCV001194164	pathogenic	Cystic fibrosis	2019-11-11	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1477C>T(Q493*) 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 23974870 and 18456578. Classification of NM_000492.3(CFTR):c.1477C>T(Q493*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Johns Hopkins Genomics, Johns Hopkins University	RCV000007526	SCV001425421	pathogenic	Cystic fibrosis	2020-04-22	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007526	SCV001584833	pathogenic	Cystic fibrosis	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln493*) 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 (rs77101217, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 1376016, 2236053, 12815607, 21184098, 21858268, 23974870). ClinVar contains an entry for this variant (Variation ID: 7107). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000727628	SCV002019237	pathogenic	not provided	2022-08-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000727628	SCV002525771	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288473	SCV002580562	pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-12-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007526	SCV002699476	pathogenic	Cystic fibrosis	2022-06-13	criteria provided, single submitter	clinical testing	The p.Q493* pathogenic mutation (also known as c.1477C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1477. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation was originally described in an individual with cystic fibrosis (clinical criteria were not provided) and pancreatic insufficiency (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). This mutation was also observed in conjunction with the (TG)12-5T variant in a male with congenital bilateral absence of the vas deferens (CBAVD); however, phase was not determined (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). This mutation is associated with pancreatic insufficiency, pulmonary disease, and elevated sweat chloride levels (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.
Fulgent Genetics, Fulgent Genetics	RCV002496294	SCV002811685	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-03-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000007526	SCV003835609	pathogenic	Cystic fibrosis	2021-02-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003472999	SCV004213276	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-19	criteria provided, single submitter	clinical testing
OMIM	RCV000007526	SCV000027727	pathogenic	Cystic fibrosis	1990-11-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000007526	SCV002029136	not provided	Cystic fibrosis		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-23-2020 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV001835623	SCV002080602	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing