Submissions for variant NM_000492.4(CFTR):c.1584G>A (p.Glu528=)

gnomAD frequency: 0.01670  dbSNP: rs1800095

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000036518	SCV000110847	benign	not specified	2014-10-17	criteria provided, single submitter	clinical testing
Invitae	RCV000231696	SCV000284997	benign	Cystic fibrosis	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001027903	SCV000466516	likely benign	CFTR-related disorders	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000422767	SCV000511145	likely benign	not provided	2016-09-21	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
GeneDx	RCV000036518	SCV000512574	likely benign	not specified	2017-12-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000422767	SCV000602998	likely benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000231696	SCV000886894	likely benign	Cystic fibrosis	2019-08-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000422767	SCV000889291	likely benign	not provided	2022-12-19	criteria provided, single submitter	clinical testing
CFTR-France	RCV000231696	SCV001169175	benign	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation	the variant does not result in CFTR-RD neither
Ambry Genetics	RCV000231696	SCV001172721	benign	Cystic fibrosis	2017-04-17	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000422767	SCV001334750	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CFTR: BP4, BS1, BS2
Genome-Nilou Lab	RCV000231696	SCV001737309	likely benign	Cystic fibrosis	2021-06-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001588847	SCV001822063	uncertain significance	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000422767	SCV002499183	uncertain significance	not provided	2022-01-18	criteria provided, single submitter	clinical testing	BS2, PS3_supporting, PM3
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000231696	SCV002507360	uncertain significance	Cystic fibrosis	2020-07-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000119037	SCV002529681	benign	Hereditary pancreatitis	2020-09-01	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000231696	SCV002573929	uncertain significance	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 2 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: PS3_SUP, BS1, BS2, BP7
PreventionGenetics, part of Exact Sciences	RCV003974873	SCV004793380	benign	CFTR-related condition	2019-04-01	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036518	SCV000060173	not provided	not specified	2013-09-27	no assertion provided	clinical testing	Glu528Glu in exon 11 of CFTR (c.1584G>A, historically known as c.1716G>A): This variant has been shown to result in exon skipping in about 10% of transcripts; however, it is prevalent in many populations (highest allele frequency 6.3% in Puerto Ricans; 1000 Genomes Project; rs1800095) and therefore not expected to cause highly penetrant, Mendelian disease. Consistent with this, it has been identified in combination with a severe CF-causing variant in control populations (Rosendahl 2013). However, several studies have suggested that it may be a predisposing factor to idiopathic chronic pancreatitis, although it is unclear if this predisposition is statistically significant (Casals 2004; Rosendahl 2013; Maire 2003). In summary, this variant may be a risk factor for CF-related disease (chronic pancreatitis). It is not expected to lead to disease on its own or in combination with a pathogenic CFTR variant, but may act in conjunction with other genetic and/or environmental risk factors.
GeneReviews	RCV000119037	SCV000153743	not provided	Hereditary pancreatitis		no assertion provided	literature only
GenomeConnect, ClinGen	RCV000844954	SCV000986779	not provided	Pancreatitis		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 02/20/2018 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.
Natera, Inc.	RCV001027903	SCV001190626	likely benign	CFTR-related disorders	2019-05-20	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001027903	SCV002507444	uncertain significance	CFTR-related disorders	2020-07-23	no assertion criteria provided	clinical testing