ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2657+5G>A (rs80224560)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000043564 SCV000071401 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000043564 SCV000071570 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000487256 SCV000331119 pathogenic not provided 2017-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000487256 SCV000567676 pathogenic not provided 2018-02-15 criteria provided, single submitter clinical testing The c.2657+5G>A variant in the CFTR gene (also reported as c.2789+5G>A due to alternate nomenclature) has been reported previously as a pathogenic variant, with a variant frequency of 0.38% among individuals with clinically diagnosed cystic fibrosis (McKone et al., 2003; Watson et al., 2004; De Boeck et al., 2014). Functional studies have shown that c.2657+5G>A causes aberrant splicing and results in the skipping of exon 16. Also, very low levels of CFTR are expressed in mutant cell lines (Masvidal et al., 2014; Sharma et al., 2014). The c.2657+G>A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2657+5G>A as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507493 SCV000603041 pathogenic not specified 2018-10-05 criteria provided, single submitter clinical testing The CFTR c.2657+5G>A variant (rs80224560), also known as 2789+5G>A, is reported in the medical literature in multiple individuals with cystic fibrosis (CF), with 53% of those individuals diagnosed with the pancreatic sufficient form of CF (Sosnay 2013). This variant is reported in ClinVar (Variation ID: 38497), and found in the general population with an overall allele frequency of 0.007% (20/277224 alleles) in the Genome Aggregation Database. Computational analyses (Alamut v.2.11) predict that the variant alters splicing, and functional studies reveal that the variant leads to the production of an aberrant transcript, while reducing full-length transcripts to 4% of normal levels (Highsmith 1997). Based on available information, this variant is considered to be moderately pathogenic. REFERENCES Highsmith WE Jr et al. Identification of a splice site mutation (2789 +5 G > A) associated with small amounts of normal CFTR mRNA and mild cystic fibrosis. Hum Mutat. 1997; 9(4):332-8. 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000043564 SCV000746541 pathogenic Cystic fibrosis 2017-12-03 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000043564 SCV000883111 pathogenic Cystic fibrosis 2018-11-21 criteria provided, single submitter clinical testing
Mendelics RCV000043564 SCV000886195 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763579 SCV000894418 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000507493 SCV000919153 pathogenic not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: CFTR c.2657+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 7.2e-05 in 277224 control chromosomes. The c.2657+5G>A variant has been reported in the literature in multiple individuals affected with Cystic Fibrosis. These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000043564 SCV000967659 pathogenic Cystic fibrosis 2018-03-07 criteria provided, single submitter clinical testing The c.2657+5G>A variant in CFTR represents 0.3-0.48% of alleles identified in in dividuals with cystic fibrosis (McKone 2003, Watson 2004, Boeck 2014). RNA studi es have shown that the c.2657+5G>A causes aberrant splicing, resulting in the sk ipping of exons 15 and 16 and leading to a significantly decreased expression of CFTR (Masvidal 2014, Sharma 2014). Accordingly, this variant is considered as a class V variant, leading to reduced amounts of functioning CFTR protein. It has been identified in 19/126716 European chromosomes by the Genome Aggregation Dat abase (gnomAD,; dbSNP rs80224560). Although thi s variant has been seen in the general population, its frequency is low enough t o be consistent with a recessive carrier frequency. Moreover, the c.2657+5G>A va riant was classified as Pathogenic on March 3, 2004 by the American College of M edical Genetics and Genomics (ClinVar SCV000071401.2). In summary, the c.2657+5G >A variant meets criteria to be classified as pathogenic for CFTR-related disord ers, including cystic fibrosis, in an autosomal recessive manner based upon its frequency in affected individuals and functional evidence. ACMG/AMP Criteria app lied (Richards 2015): PS3, PS4.
Baylor Genetics RCV001004484 SCV001163529 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009372 SCV001169225 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Ambry Genetics RCV001016230 SCV001177160 pathogenic Inborn genetic diseases 2019-05-01 criteria provided, single submitter clinical testing 2 of classification of c (below) met (2c = 1b);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;Other strong data supporting pathogenic classification ;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Myriad Women's Health, Inc. RCV000043564 SCV001194228 pathogenic Cystic fibrosis 2019-11-12 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.2657+5G>A(aka 2789+5G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with a non-classic form of disease. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.2657+5G>A(aka 2789+5G>A) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Johns Hopkins Genomics,Johns Hopkins University RCV000043564 SCV001425390 pathogenic Cystic fibrosis 2020-02-19 criteria provided, single submitter clinical testing Disease-causing CFTR variant. See for phenotype information.

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