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

gnomAD frequency: 0.00006  dbSNP: rs80224560

Total submissions: 33

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
Eurofins Ntd Llc (ga)	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	RCV000487256	SCV000603041	pathogenic	not provided	2023-04-05	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 about half of those individuals diagnosed with the pancreatic sufficient form of CF (Sosnay 2013). This variant is reported in ClinVar (Variation ID: 38497), and is found in the general population with an overall allele frequency of 0.007% (20/282870 alleles) in the Genome Aggregation Database. Computational analyses (Alamut v.2.11) predict that this 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 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. PMID: 9101293. 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.
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	2022-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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, Mass General Brigham 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, http://gnomad.broadinstitute.org; 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 disorder	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	RCV000043564	SCV001177160	pathogenic	Cystic fibrosis	2022-05-12	criteria provided, single submitter	clinical testing	The c.2657+5G>A intronic pathogenic mutation (also known as 2789+5G>A) results from a G to A substitution 5 nucleotides after coding exon 16 in the CFTR gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration was reported in 88 individuals with cystic fibrosis, of which 61 were compound heterozygous with p.F508del; these individuals had elevated sweat chloride levels, pulmonary symptoms, normal gastrointestinal function, and approximately 60% were pancreatic insufficient (Dugu&eacute;p&eacute;roux I et al. Eur. Respir. J., 2005 Mar;25:468-73). In another study, individuals who were homozygous for this mutation in a consanguineous family presented with mild obstructive lung disease, abnormal sweat chloride levels, and pancreatic sufficiency. In addition, mRNA levels in the nasal epithelium from these individuals were 4% of wild-type (Highsmith WE et al. Hum. Mutat., 1997;9:332-8). An in vitro minigene assay had concordant findings and showed that this mutation reduces protein expression to <10% of wild type (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.
Myriad Genetics, 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 www.CFTR2.org for phenotype information.
Baylor Genetics	RCV000043564	SCV001523281	pathogenic	Cystic fibrosis	2019-05-08	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043564	SCV001586033	pathogenic	Cystic fibrosis	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change falls in intron 16 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80224560, gnomAD 0.01%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 12767731, 17347447, 19550280, 21520337, 22020151, 23751316, 23974870, 25122143). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2789+5G>A. ClinVar contains an entry for this variant (Variation ID: 38497). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24129438, 25066652). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000487256	SCV001715955	pathogenic	not provided	2020-10-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487256	SCV001747526	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	CFTR: PM3:Very Strong, PM2, PS1:Supporting, PS3:Supporting
Revvity Omics, Revvity	RCV000487256	SCV002019222	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257369	SCV002529700	pathogenic	Hereditary pancreatitis	2021-04-06	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000043564	SCV002574060	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 4 unrelated patients 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: PS1_SUP, PS3, PM2_SUP, PM3_STR, PP3, PP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000043564	SCV003921835	pathogenic	Cystic fibrosis	2020-07-22	criteria provided, single submitter	clinical testing	0102 - Loss of function is a known mechanism of disease in this gene and is associated with cystic fibrosis (MIM#219700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Mini gene assays and ex vivo studies demonstrated that the variant results in the skipping of exon 16 (PMID: 24129438). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (20 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has been widely reported as pathogenic in autosomal recessive cystic fibrosis (MIM#219700). It is considered to be a class V variant, resulting in partially impaired protein function and is associated with a milder phenotype (ClinVar, PMID: 24129438). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV003473241	SCV004213299	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487256	SCV004221677	pathogenic	not provided	2023-07-14	criteria provided, single submitter	clinical testing	The CFTR c.2657+5G>A variant has been reported in the published literature in the homozygous state or compound heterozygous state with other CF variants in individuals with CF and CF-related disorders (PMIDs: 12767731 (2003), 15371902 (2004), 15738290 (2005), 17347447 (2007), 22658665 (2012), 24440181 (2014), 24129438 (2014), 25122143 (2015)). Functional studies have described this variant as a Class V variant, causing aberrant splicing, exon 16 skipping, and partial loss of the CFTR protein (PMIDs: 9101293 (1997), 24129438 (2014), 25066652 (2014)). The frequency of this variant in the general population, 0.00078 (9/11610 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper CFTR mRNA splicing. Based on the available information, this variant is classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000043564	SCV004801203	pathogenic	Cystic fibrosis	2024-03-14	criteria provided, single submitter	research
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000487256	SCV005197459	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
GeneReviews	RCV000043564	SCV001622802	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000487256	SCV001742688	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000487256	SCV001975162	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001835639	SCV002080785	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001835639	SCV005361750	pathogenic	CFTR-related disorder	2024-04-04	no assertion criteria provided	clinical testing	The CFTR c.2657+5G>A variant is predicted to interfere with splicing. This variant (also known as 2789+5G>A in the literature) is predicted and functionally proven to result in aberrant splicing and skipping of exon 16 due to disruption of the splice donor site (Masvidal et al. 2014. PubMed ID: 24129438). This variant has been previously reported to be causative for cystic fibrosis (e.g., Duguépéroux and Braekeleer. 2005. PubMed ID: 15738290;  Masvidal et al. 2014. PubMed ID: 24129438; Supplementary data, Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.