ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3909C>G (p.Asn1303Lys) (rs80034486)

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Total submissions: 20
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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 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1303 of the CFTR protein (p.Asn1303Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs80034486, ExAC 0.02%). This variant has been reported in many individuals and families affected with CFTR-related disorders, including cystic fibrosis, congenital bilateral absence of the vas deferens, and chronic pancreatitis (PMID: 23951356, 23974870, 21520337). It is one of the most common pathogenic variants in CFTR (PMID: 1380943, 12767731, 15371902, 22658665). ClinVar contains an entry for this variant (Variation ID: 7136). Experimental studies have shown that this missense change disrupts CFTR protein maturation and abolishes ion channel function when expressed in cell culture (PMID: 23974870, 23891399, 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 Clinical Services Laboratory,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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 RCV000999853 SCV000885186 pathogenic not specified 2018-07-27 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, and often associated with pancreatic insufficiency (Osborne 1991, Osborne 1992, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported as pathogenic by multiple laboratories 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 (SIFT, PolyPhen-2) predict that this variant is deleterious. 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 severely pathogenic. References: CFTR2 database: http://cftr2.org Ooi C. et al. (2012) Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 11(5):355-62. Osborne L et al. (1991) A mutation in the second nucleotide binding fold of the cystic fibrosis gene. Am J Hum Genet. 48(3):608-12. Osborne L et al. (1992) Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene. Hum Genet. 89(6):653-8. Sosnay PR et al. (2013) Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 45(10):1160-7. Van Goor F et al. (2014) Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 13(1):29-36.
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 RCV001021411 SCV001183025 pathogenic Inborn genetic diseases 2019-02-05 criteria provided, single submitter clinical testing Deficient protein function by in vitro/ex vivo assay;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Undiagnosed Diseases Network,NIH RCV000007556 SCV001245580 pathogenic Cystic fibrosis 2018-10-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224445 SCV001246824 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
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.

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