ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.254G>A (p.Gly85Glu) (rs75961395)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000007563 SCV000071400 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000007563 SCV000071502 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224170 SCV000281534 pathogenic not provided 2015-11-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224170 SCV000700671 pathogenic not provided 2017-02-07 criteria provided, single submitter clinical testing
Mendelics RCV000007563 SCV000886181 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000224170 SCV000888081 pathogenic not provided 2016-08-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002050 SCV001159876 pathogenic not specified 2018-08-21 criteria provided, single submitter clinical testing The CFTR c.254G>A, p.Gly85Glu variant (rs75961395) is reported in multiple unrelated patients diagnosed with cystic fibrosis (Chalkley 1991, Zielenski 1991, Kerem 1997, Gallati 2009, Chavez-Saldana 2010, Ooi 2012, CFTR2 database). However, the clinical presentations of these patients are highly variable, ranging from severe lung disorder and pancreatic insufficiency, to mild respiratory symptoms and pancreatic sufficiency (Chalkley 1991, Kerem 1997). Functional characterization of the variant protein indicates a failure in trafficking to the cell surface (Patrick 2011, Sosnay 2013, Van Goor 2014), due to aberrant integration of the protein in the endoplasmic reticulum (Patrick 2011). The variant is described in the ClinVar database (Variation ID: 7143) and in the Genome Aggregation Database in 12 out of 276578 alleles. The glycine at residue 85 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has a deleterious impact on the protein. Considering available information, the variant is classified as pathogenic. References: Link to CFTR2 database: Chalkley G et al. A cystic fibrosis patient who is homozygous for the G85E mutation has very mild disease. J Med Genet. 1991 28(12):875-7. Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010 62(6):546-52. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. Kerem B et al. A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype. Pediatrics. 1997 100(3):E5. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. Patrick A et al. Alteration of CFTR transmembrane span integration by disease-causing mutations. Mol Biol Cell. 2011 22(23):4461-71. 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. 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. Zielenski J et al. Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991 May;10(1):229-35.
Baylor Genetics RCV001004234 SCV001163110 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000007563 SCV001169502 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001015924 SCV001176818 pathogenic Inborn genetic diseases 2019-01-25 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;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Myriad Women's Health, Inc. RCV000007563 SCV001193848 pathogenic Cystic fibrosis 2019-11-15 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.254G>A(G85E) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.254G>A(G85E) 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.
OMIM RCV000007563 SCV000027764 pathogenic Cystic fibrosis 1991-12-01 no assertion criteria provided literature only

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