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NM_000492.3(CFTR):c.3205G>A (p.Gly1069Arg)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(2);Pathogenic(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
6 (Most recent: Mar 28, 2019)
Last evaluated:
Oct 9, 2018
Accession:
VCV000053684.2
Variation ID:
53684
Description:
single nucleotide variant
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NM_000492.3(CFTR):c.3205G>A (p.Gly1069Arg)

Allele ID
68352
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7q31.2
Genomic location
7: 117611646 (GRCh38) GRCh38 UCSC
7: 117251700 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000007.13:g.117251700G>A
NC_000007.14:g.117611646G>A
NM_000492.3:c.3205G>A NP_000483.3:p.Gly1069Arg
... more HGVS
Protein change
G1069R
Other names
-
Functional consequence
-
Global minor allele frequency (GMAF)
0.00040 (A)

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00023
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
1000 Genomes Project 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00026
Trans-Omics for Precision Medicine (TOPMed) 0.00028
The Genome Aggregation Database (gnomAD) 0.00035
Links
dbSNP: rs200321110
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Oct 9, 2018 RCV000046823.4
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Aug 18, 2017 RCV000506564.3
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CFTR - - GRCh38
GRCh37
1299 1828
LOC111674472 - - - GRCh38 - 174

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Jun 30, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601092.1
Submitted: (Aug 01, 2017)
Evidence details
Publications
PubMed (30)
Likely pathogenic
(Dec 01, 2016)
criteria provided, single submitter
Method: clinical testing
Cystic fibrosis
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000696958.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (18)
Comment:
Variant summary: The CFTR c.3205G>A (p.Gly1069Arg) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. ... (more)
Uncertain significance
(Nov 22, 2017)
criteria provided, single submitter
Method: clinical testing
Cystic fibrosis
Allele origin: unknown
Counsyl
Accession: SCV000795750.1
Submitted: (Jul 10, 2018)
Evidence details
Publications
PubMed (5)
Uncertain significance
(Apr 12, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000331451.4
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/em...
Pathogenic
(Aug 18, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
Accession: SCV000603016.2
Submitted: (Oct 10, 2018)
Evidence details
Comment:
The CFTR c.3205G>A, p.Gly1069Arg variant (rs200321110) has been reported in multiple patients diagnosed with CFTR-related disorders (Ratbi 2007, Masson 2013). It has also been reported ... (more)
Uncertain significance
(Oct 09, 2018)
criteria provided, single submitter
Method: clinical testing
Cystic fibrosis
Allele origin: germline
Invitae
Accession: SCV000074836.5
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (11)
Comment:
This sequence change replaces glycine with arginine at codon 1069 of the CFTR protein (p.Gly1069Arg). The glycine residue is moderately conserved and there is a ... (more)

Citations for this variant

Title Author Journal Year Link
Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics. Soltysova A The clinical respiratory journal 2018 PMID: 28544683
Early-Onset Acute Recurrent and Chronic Pancreatitis Is Associated with PRSS1 or CTRC Gene Mutations. Giefer MJ The Journal of pediatrics 2017 PMID: 28502372
A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. Lucarelli M Molecular medicine (Cambridge, Mass.) 2015 PMID: 25910067
Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment. Chang MC Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2015 PMID: 25869325
Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics. Mornon JP Cellular and molecular life sciences : CMLS 2015 PMID: 25287046
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. Tabor HK American journal of human genetics 2014 PMID: 25087612
Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. LaRusch J PLoS genetics 2014 PMID: 25033378
Allosteric coupling between the intracellular coupling helix 4 and regulatory sites of the first nucleotide-binding domain of CFTR. Dawson JE PloS one 2013 PMID: 24058550
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Sosnay PR Nature genetics 2013 PMID: 23974870
A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. Masson E PloS one 2013 PMID: 23951356
Functional Rescue of F508del-CFTR Using Small Molecule Correctors. Molinski S Frontiers in pharmacology 2012 PMID: 23055971
Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect. Dong Q Proceedings of the National Academy of Sciences of the United States of America 2012 PMID: 22210114
CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pelletier AL Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 2010 PMID: 20460946
Validation of high-resolution DNA melting analysis for mutation scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Audrezet MP The Journal of molecular diagnostics : JMD 2008 PMID: 18687795
Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Serohijos AW Proceedings of the National Academy of Sciences of the United States of America 2008 PMID: 18305154
Cystic fibrosis in a southern Brazilian population: characteristics of 90% of the alleles. Faucz FR Clinical genetics 2007 PMID: 17718859
Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. Chang MC Clinical genetics 2007 PMID: 17539902
Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Ratbi I Human reproduction (Oxford, England) 2007 PMID: 17329263
Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Keiles S Pancreas 2006 PMID: 17003641
Gender-sensitive association of CFTR gene mutations and 5T allele emerging from a large survey on infertility. Morea A Molecular human reproduction 2005 PMID: 16126774
Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations. Schrijver I The Journal of molecular diagnostics : JMD 2005 PMID: 16049310
Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype. De Boeck K Pediatrics 2005 PMID: 15772171
Reduced CFTR function and the pathobiology of idiopathic pancreatitis. Cohn JA Journal of clinical gastroenterology 2005 PMID: 15758663
Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening. Bobadilla JL Human mutation 2002 PMID: 12007216
Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Noone PG Gastroenterology 2001 PMID: 11729110
Insulin improves clinical status of patients with cystic-fibrosis-related diabetes mellitus. Nousia-Arvanitakis S Acta paediatrica (Oslo, Norway : 1992) 2001 PMID: 11430710
Increased frequency of CFTR gene mutations in sarcoidosis: a case/control association study. Bombieri C European journal of human genetics : EJHG 2000 PMID: 10980579
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Claustres M Human mutation 2000 PMID: 10923036
Cystic fibrosis mutations and associated haplotypes in Bulgaria - a comparative population genetic study. Angelicheva D Human genetics 1997 PMID: 9099843
Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. Cotten JF The Journal of biological chemistry 1996 PMID: 8702904
Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. Seibert FS The Journal of biological chemistry 1996 PMID: 8662892
Double mutant alleles: are they rare? Savov A Human molecular genetics 1995 PMID: 8528204
A cluster of cystic fibrosis mutations in exon 17b of the CFTR gene: a site for rare mutations. Mercier B Journal of medical genetics 1994 PMID: 7529319
Identification of six novel mutations in the CFTR gene of patients from Bulgaria by screening the twenty seven exons and exon/intron boundaries using DGGE and direct DNA sequencing. Savov A Human molecular genetics 1994 PMID: 7512860
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR - - - -

Record last updated Sep 08, 2019