Submissions for variant NM_000492.4(CFTR):c.4426C>T (p.Gln1476Ter)

gnomAD frequency: 0.00002  dbSNP: rs374705585

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000388068	SCV000331003	pathogenic	not provided	2013-08-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000505964	SCV000602994	pathogenic	not specified	2016-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047135	SCV000697026	pathogenic	Cystic fibrosis	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.4426C>T (p.Gln1476X) variant results in a termination codon in the penultimate exon deleting the last four amino acids (Asp-Thr-Arg-Leu). No pathogenic/likely pathogenic truncating variants downstream of this position have been reported in literature, ClinVar and our laboratory and it is outside of some of the commonly known domains (transmembrane domain, ATPase domain and regulator domain) (InterPro). There are no functional studies for this variant as well. Mutation taster predicts a damaging outcome for this variant. This variant was found in 3/120070 control chromosomes including ExAC at a frequency of 0.000025, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In literature, this variant was found in at least 5 CF patients, 5 CBAVD patients, 3 ICP patients and 3 patients reported to be diagnosed of CFTR-RD. Most patients were known to be compound heterozygotes with another pathogenic variant, primarily with p.Phe508del. In addition, two reported CBAVD patients were found to have elevated sweat chloride implying the diagnosis of CF/NC. Although a nonsense variant, severity of disease associated with this variant is widely reported as mild in literature which can be implicated to its location and resuting functional consequence. One clinical laboratory in ClinVar has classified it as pathogenic. Because CF/NC phenotype has been reported with this variant, and because CBAVD and ICP can also be categorized as manifestation of CF, this variant has been classified as pathogenic with respect to CF/NC phenotype.
Baylor Genetics	RCV001004311	SCV001163188	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009479	SCV001169574	pathogenic	CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation
Invitae	RCV000047135	SCV001582233	pathogenic	Cystic fibrosis	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1476*) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the CFTR protein. This variant is present in population databases (rs374705585, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 11938439, 22020151, 25910067, 28544683). ClinVar contains an entry for this variant (Variation ID: 53947). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CFTR function (PMID: 30444886). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000047135	SCV001984855	likely pathogenic	Cystic fibrosis	2020-05-27	criteria provided, single submitter	clinical testing	This variant affects the last exon of CFTR and is predicted to escape nonsense mediated decay (NMD). The c.4426C>T alteration has been previously reported as a compound heterozygous change in multiple patients with variable clinical presentation ranging from cystic fibrosis to congenital absence of vas deference, and other CFTR-related disorders such as chronic pancreatitis (PMID: 21520337, 22020151, 23276700, https://cftr2.org/mutation/general/all_cf/Q1476X). In-vitro studies showed that this variant leads to the expression of a mature truncated form of CFTR that moderately affects the channel functioning and is responsive to treatment with lumacaftor, or a combination of both lumacaftor and tezacaftor (PMID: 30444886). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/282280) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.4426C>T (p.Gln1476Ter) variant on protein function. Based on the available evidence, the c.4426C>T (p.Gln1476Ter) variant is classified as Likely Pathogenic.
Mendelics	RCV002247439	SCV002518693	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002247439	SCV002529734	pathogenic	Hereditary pancreatitis	2021-05-10	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000047135	SCV002573879	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_MOD, PS3_SUP, PM2_SUP, PM3_STR, PP4
Ambry Genetics	RCV000047135	SCV002628136	likely pathogenic	Cystic fibrosis	2023-05-31	criteria provided, single submitter	clinical testing	The p.Q1476* variant (also known as c.4426C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4426. This changes the amino acid from a glutamine to a stop codon within coding exon 27. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of CFTR, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 5 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. However, this variant has been reported in the literature in several individuals who are compound heterozygous for p.Q1476* and p.F508del: one individual with idiopathic pancreatitis was subsequently found to have elevated sweat chloride levels (Audrézet MP et al. Eur. J. Hum. Genet., 2002 Feb;10:100-6), two males had elevated sweat chloride levels, congenital bilateral absence of the vas deferens (CBAVD), pancreatic sufficiency, and normal respiratory function (Bienvenu T et al. Clin. Genet., 2003 Sep;64:266-8), a third male was reported to have CBAVD only (Amato F et al. J Mol Diagn, 2012 Jan;14:81-9), another individual had moderate pulmonary symptoms with nasal polyposis and digital clubbing (Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206), and the last individual had a history of bronchiectasis and pseudomonas infection (Sugunaraj JP et al. NPJ Genom Med, 2019 Sep;4:21). This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 4, 2019). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000388068	SCV002756476	likely pathogenic	not provided	2022-05-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost within the PDZ interaction domain (Moyer et al., 1999), although loss-of-function variants have not been reported downstream of this position in the protein; Published functional studies demonstrate normal protein expression and modulator response, but reduced chloride channel function (Sharma et al., 2018); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31589614, 34426522, 30444886, 11938439, 12919146, 10562297, 17449517, 28603918, 21520337, 23276700, 25910067, 22020151, 25087612, 28544683, 21679131, 16784904, 17003641, 12578973, 11504857, 15758663)
Fulgent Genetics, Fulgent Genetics	RCV002477161	SCV002779186	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-03-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466915	SCV004215790	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2022-02-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000388068	SCV004221701	pathogenic	not provided	2022-10-21	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of CFTR protein synthesis. The frequency of this variant in the general population, 0.000039 (5/128820 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMIDs: 28544683 (2017), 23276700 (2013), 12919146 (2003), 11938439 (2002)) and cystic fibrosis related disease (CFRD) (PMIDs: 25910067 (2015), 22020151 (2012), 21679131 (2011), 21520337 (2011), 17449517 (2007), 17003641 (2006), 12919146 (2003)). This variant is often detected in trans with another pathogenic CFTR variant in affected individuals (PMIDs: 28544683 (2017), 25910067 (2015), 22020151 (2012)). Functional studies have demonstrated this variant may mildly impact protein function, but additional studies are needed to determine the global impact of this variant on the CFTR gene or gene products (PMID: 30444886 (2018)). Based on the available information, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000388068	SCV004811459	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	CFTR: PM3:Very Strong, PM2, PVS1:Moderate
Counsyl	RCV000047135	SCV001132152	uncertain significance	Cystic fibrosis	2018-12-19	no assertion criteria provided	clinical testing
Baylor Genetics	RCV000047135	SCV002583263	pathogenic	Cystic fibrosis		no assertion criteria provided	clinical testing