Submissions for variant NM_000492.4(CFTR):c.3909C>G (p.Asn1303Lys)

gnomAD frequency: 0.00016  dbSNP: rs80034486

Total submissions: 40

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000007556	SCV000071408	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission to Pathogenic.
CFTR2	RCV000007556	SCV000071513	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Invitae	RCV000007556	SCV000075041	pathogenic	Cystic fibrosis	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1303 of the CFTR protein (p.Asn1303Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with CFTR-related disorders, including cystic fibrosis, congenital bilateral absence of the vas deferens, and chronic pancreatitis (PMID: 1380943, 12767731, 15371902, 21520337, 22658665, 23951356, 23974870). ClinVar contains an entry for this variant (Variation ID: 7136). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23974870, 25799511). For these reasons, this variant has been classified as Pathogenic.
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000007556	SCV000236515	pathogenic	Cystic fibrosis	2014-08-29	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224445	SCV000280980	pathogenic	not provided	2015-02-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000224445	SCV000322329	pathogenic	not provided	2018-12-31	criteria provided, single submitter	clinical testing	The N1303K variant in the CFTR gene has been reported previously as a CF-causing variant in patients with abnormal sweat chloride levels, pancreatic insufficiency, and mild to moderate lung disease (Sosnay et al., 2013; Osborne et al, 1991). The N1303K variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N1303K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the ABC transporter 2 domain that is conserved across species. Cell lines expressing the N1303K CFTR variant show loss of baseline chloride transport compared to those expressing wild type protein (Van Goor et al., 2014). A missense variant at the same residue, N1303H, was reported in a patient with severe pulmonary disease and pancreatic insufficiency (Claustres et al., 1992). We interpret N1303K as a pathogenic variant.
Illumina Laboratory Services, Illumina	RCV000007556	SCV000466525	pathogenic	Cystic fibrosis	2017-09-05	criteria provided, single submitter	clinical testing	The CFTR c.3909C>G (p.Asn1303Lys) missense variant is a well-known, widely reported pathogenic variant that accounts for approximately 1.3% of disease alleles, and is often associated with a classic cystic fibrosis (CF) phenotype (Ong et al. 2001). The Cystic Fibrosis Mutation Database (http://www.genet.sickkids.on.ca/cftr/Home.html) indicates that the p.Asn1303Lys variant is the fourth most common CFTR variant worldwide, and the Clinical and Functional Translation of CFTR (CFTR2) database (http://cftr2.org) reports the p.Asn1303Lys variant in over 2100 patients, noting that it is a cystic fibrosis-causing variant. Across a selection of the available literature, the p.Asn1303Lys variant has also been reported in five patients with congenital bilateral absence of the vas deferens (CBAVD), including three compound heterozygotes and two heterozygotes in whom a second variant was not identified (Steiner et al. 2011; Tomaiuolo et al. 2011), and in four patients with chronic pancreatitis, including three compound heterozygotes and one heterozygote (Steiner et al. 2011; Hamoir et al. 2013). The p.Asn1303Lys variant is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Asn1303Lys 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.
Counsyl	RCV000007556	SCV000485189	pathogenic	Cystic fibrosis	2016-02-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000224445	SCV000700266	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000007556	SCV000807601	pathogenic	Cystic fibrosis	2017-09-01	criteria provided, single submitter	clinical testing	This mutation has been previously reported as disease-causing and was found once in our laboratory in a homozygous state in a 13-year-old male with a clinical diagnosis of cystic fibrosis. Heterozygotes are expected to be asymptomatic carriers.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000007556	SCV000883112	pathogenic	Cystic fibrosis	2018-11-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224445	SCV000885186	pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing	The CFTR c.3909C>G; p.Asn1303Lys variant (rs80034486), is reported in the literature in multiple individuals diagnosed with cystic fibrosis, often associated with pancreatic insufficiency (Osborne 1991, Osborne 1992, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 7136), and is found in the general population with an overall allele frequency of 0.014% (34/244424 alleles) in the Genome Aggregation Database. The asparagine at codon 1303 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.83). Functional characterization of the variant protein indicates a defect in CFTR processing, resulting in a severe reduction in chloride transport activity (Sosnay 2013, Van Goor 2014). Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. PMID: 22658665 Osborne L et al. A mutation in the second nucleotide binding fold of the cystic fibrosis gene. Am J Hum Genet. 1991 48(3):608-12. PMID: 1998343 Osborne L et al. Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene. Hum Genet. 1992 89(6):653-8. PMID: 1380943 Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. PMID: 23974870 Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 13(1):29-36. PMID: 23891399
Mendelics	RCV000007556	SCV000886186	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004513	SCV001163558	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007556	SCV001169352	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000007556	SCV001183025	pathogenic	Cystic fibrosis	2022-02-18	criteria provided, single submitter	clinical testing	The p.N1303K pathogenic mutation (also known as c.3909C>G), located in coding exon 24 of the CFTR gene, results from a C to G substitution at nucleotide position 3909. The asparagine at codon 1303 is replaced by lysine, an amino acid with similar properties. In one study, this mutation was identified in 216 cystic fibrosis alleles, including 10 homozygous individuals with elevated sweat chloride levels and decreased lung function. Of the 6 homozygous individuals with reported pancreatic status, all were pancreatic insufficient (Osborne L et al. Hum. Genet., 1992 Aug;89:653-8). In vitro functional studies determined that this mutation prevents the maturation, trafficking, and subsequent activity of the CFTR protein (Gregory RJ et al. Mol. Cell. Biol., 1991 Aug;11:3886-93). This pathogenic mutation is associated with elevated sweat chloride levels, decreased lung function, and pancreatic insufficiency; in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Undiagnosed Diseases Network, NIH	RCV000007556	SCV001245580	pathogenic	Cystic fibrosis	2018-10-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224445	SCV001246824	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000224445	SCV001450061	pathogenic	not provided	2019-05-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224445	SCV001713441	pathogenic	not provided	2021-01-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000224445	SCV002019227	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000007556	SCV002507341	pathogenic	Cystic fibrosis	2019-09-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255995	SCV002529722	pathogenic	Hereditary pancreatitis	2021-05-25	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007556	SCV002573872	pathogenic	Cystic fibrosis	2023-07-26	criteria provided, single submitter	curation	This variant was classified based on the report of 1 patient with a clinically confirmed diagnosis of cystic fibrosis in the context of re-classifying variants in the German Cystic Fibrosis Registry (Muko e.V.). Patients have not been seen personally, but only reports were evaluated. Criteria applied: PS3, PM2_SUP, PM3_VSTR, PM5_STR, PP3, PP4
Institute of Human Genetics, University Hospital Muenster	RCV002287325	SCV002577968	pathogenic	Spermatogenic failure, Y-linked, 2	2018-06-07	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PS4,PP3,PP5
MGZ Medical Genetics Center	RCV000007556	SCV002580775	pathogenic	Cystic fibrosis	2022-04-27	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000007556	SCV002758574	pathogenic	Cystic fibrosis	2022-09-23	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PS3, PS4, PP3, PP1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000224445	SCV004026196	pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473015	SCV004213314	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224445	SCV004221697	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00018 (23/128054 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in the homozygous state and with other CF variants in trans to be particularly associated with a pancreatic insufficient phenotype, however, variable lung function phenotypes from unusually mild to severe have been observed (PMID: 1380943 (1992), 23974870 (2013), and 26208274 (2015)). Functional analysis has described this variant as Class II causing defective protein processing, protein degradation, insignificant levels of mature CFTR, and conductance (PMID: 1712898 (1991), 23891399 (2014), 25799511 (2015), 26823392 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003904815	SCV004734204	pathogenic	CFTR-related condition	2023-12-13	criteria provided, single submitter	clinical testing	The CFTR c.3909C>G variant is predicted to result in the amino acid substitution p.Asn1303Lys. This variant has been reported in many individuals to be causative for cystic fibrosis (Sosnay et al. 2013. PubMed ID: 23974870; Masson et al. 2013. PubMed ID: 23951356; Osborne et al. 1991. PubMed ID: 1998343; Watson et al. 2004. PubMed ID: 15371902). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000007556	SCV000027757	pathogenic	Cystic fibrosis	1992-08-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000007556	SCV000986698	not provided	Cystic fibrosis		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 03/20/2016 by 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.
GeneReviews	RCV000007556	SCV001622794	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224445	SCV001740653	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224445	SCV001959836	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224445	SCV001975183	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831530	SCV002075912	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001831530	SCV002507425	pathogenic	CFTR-related disorders	2019-09-25	no assertion criteria provided	clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000007556	SCV004024087	pathogenic	Cystic fibrosis		no assertion criteria provided	research