ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1584G>A (p.Glu528=)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(4); Benign(7); Likely benign(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.1584G>A (p.Glu528=)
Variation ID: 43576 Accession: VCV000043576.68
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117559655 (GRCh38) [ NCBI UCSC ] 7: 117199709 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 May 12, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1584G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Glu528= synonymous NC_000007.14:g.117559655G>A NC_000007.13:g.117199709G>A NG_016465.4:g.98872G>A LRG_663:g.98872G>A LRG_663t1:c.1584G>A LRG_663p1:p.Glu528= - Protein change
- Other names
- 1716G/A
- Canonical SPDI
- NC_000007.14:117559654:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.01058 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.01058
1000 Genomes Project 30x 0.01077
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01438
Trans-Omics for Precision Medicine (TOPMed) 0.01555
The Genome Aggregation Database (gnomAD) 0.01670
The Genome Aggregation Database (gnomAD), exomes 0.01672
Exome Aggregation Consortium (ExAC) 0.01691
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CFTR | - | - |
GRCh38 GRCh37 |
3704 | 5025 | |
CFTR-AS1 | - | - | - | GRCh38 | - | 490 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 26, 2017 | RCV000036518.24 | |
Benign (2) |
criteria provided, single submitter
|
Sep 1, 2020 | RCV000119037.11 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
Feb 1, 2024 | RCV000231696.31 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 1, 2024 | RCV000422767.43 | |
not provided (1) |
no classification provided
|
- | RCV000844954.9 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2019 | RCV001027903.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 22, 2021 | RCV001588847.10 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Dec 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000512574.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018 |
Comment:
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 … (more)
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. (less)
|
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Benign
(Oct 17, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110847.8
First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018 |
Number of individuals with the variant: 22
Sex: mixed
|
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Benign
(Sep 01, 2020)
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criteria provided, single submitter
Method: curation
|
Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529681.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
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Likely Benign
(Sep 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511145.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Likely benign.
|
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Benign
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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cystic fibrosis
Affected status: no, yes
Allele origin:
germline
|
CFTR-France
Accession: SCV001169175.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
the variant does not result in CFTR-RD neither
Observation 1: Observation 2: |
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Likely benign
(Jun 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001737309.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Sex: mixed
|
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Uncertain significance
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001822063.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
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Uncertain significance
(Jan 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002499183.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
BS2, PS3_supporting, PM3
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Uncertain significance
(Jul 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507360.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
|
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Uncertain significance
(Sep 05, 2022)
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criteria provided, single submitter
Method: curation
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002573929.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Comment:
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 … (more)
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 (less)
Number of individuals with the variant: 2
|
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Likely benign
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602998.9
First in ClinVar: Mar 08, 2017 Last updated: Feb 20, 2024 |
|
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Benign
(Apr 17, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001172721.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. (less)
|
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Likely benign
(Aug 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV000886894.2
First in ClinVar: Dec 26, 2017 Last updated: Mar 07, 2020 |
|
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Likely benign
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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CFTR-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000466516.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
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 … (more)
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. (less)
|
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Likely benign
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889291.5
First in ClinVar: Mar 08, 2017 Last updated: Jan 06, 2024 |
|
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000284997.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
|
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Benign
(Apr 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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CFTR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004793380.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
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).
|
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Benign
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334750.20
First in ClinVar: Jun 08, 2020 Last updated: May 12, 2024 |
Comment:
CFTR: BP4, BS1, BS2
Number of individuals with the variant: 18
|
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Uncertain significance
(Jul 23, 2020)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507444.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
|
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Likely benign
(May 20, 2019)
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no assertion criteria provided
Method: clinical testing
|
CFTR-related disorders
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001190626.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
|
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not provided
(-)
|
no classification provided
Method: literature only
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Hereditary pancreatitis
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000153743.3
First in ClinVar: May 31, 2014 Last updated: Oct 01, 2022 |
|
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not provided
(Sep 27, 2013)
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no classification provided
Method: clinical testing
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Not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060173.4
First in ClinVar: May 03, 2013 Last updated: Jun 28, 2015 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 6
|
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not provided
(-)
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no classification provided
Method: phenotyping only
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Pancreatitis
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV000986779.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Hyperthyroidism (present) , Myopia (present) , Anxiety (present) , Depressivity (present) , Abnormality of the pancreas (present) , Abnormality of the liver (present)
Age: 10-19 years
Sex: female
Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic
Date variant was reported to submitter: 2018-02-20
Testing laboratory interpretation: Uncertain significance
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Identification of incompletely penetrant variants and interallelic interactions in autosomal recessive disorders by a population-genetic approach. | Mikó Á | Human mutation | 2021 | PMID: 34405919 |
Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey. | Bozdogan ST | Genes | 2021 | PMID: 33572515 |
Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity. | Rauscher R | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 33468668 |
The Effect of Synonymous Single-Nucleotide Polymorphisms on an Atypical Cystic Fibrosis Clinical Presentation. | Bampi GB | Life (Basel, Switzerland) | 2020 | PMID: 33375403 |
Pancreatitis Overview. | Adam MP | - | 2020 | PMID: 24624459 |
Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience. | Şaşihüseyinoğlu AŞ | The Turkish journal of pediatrics | 2019 | PMID: 31990467 |
Pitfalls in the interpretation of CFTR variants in the context of incidental findings. | Boussaroque A | Human mutation | 2019 | PMID: 31350925 |
Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction and Radiographic Bronchiectasis in Current and Former Smokers: A Cross-Sectional Study. | Teerapuncharoen K | Annals of the American Thoracic Society | 2019 | PMID: 30230364 |
Comprehensive genetic testing for female and male infertility using next-generation sequencing. | Patel B | Journal of assisted reproduction and genetics | 2018 | PMID: 29779145 |
Pathophysiology and Genetics of Bronchiectasis Unrelated to Cystic Fibrosis. | Nikolic A | Lung | 2018 | PMID: 29754320 |
Ratiometric sweat secretion optical test in cystic fibrosis, carriers and healthy subjects. | Bergamini G | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2018 | PMID: 29292091 |
Validation of a semiconductor next-generation sequencing assay for the clinical genetic screening of CFTR. | Trujillano D | Molecular genetics & genomic medicine | 2015 | PMID: 26436105 |
Should diffuse bronchiectasis still be considered a CFTR-related disorder? | Bergougnoux A | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2015 | PMID: 25797027 |
p.Arg75Gln, a CFTR variant involved in the risk of CFTR-related disorders? | Martinez B | Journal of human genetics | 2014 | PMID: 24451227 |
CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? | Rosendahl J | Gut | 2013 | PMID: 22427236 |
Functional analysis of synonymous substitutions predicted to affect splicing of the CFTR gene. | Scott A | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2012 | PMID: 22591852 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. | Puéchal X | Annals of the rheumatic diseases | 2011 | PMID: 21131649 |
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 |
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma. | McWilliams RR | Cancer | 2010 | PMID: 19885835 |
Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. | Goubau C | Thorax | 2009 | PMID: 19318346 |
Could a defective epithelial sodium channel lead to bronchiectasis. | Fajac I | Respiratory research | 2008 | PMID: 18507830 |
Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations? | Casals T | Clinical genetics | 2004 | PMID: 15151509 |
Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? | Casals T | Pancreas | 2004 | PMID: 15097853 |
[Frequency of CFTR gene mutations in idiopathic pancreatitis]. | Maire F | Gastroenterologie clinique et biologique | 2003 | PMID: 12759680 |
Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis. | Ockenga J | The American journal of gastroenterology | 2000 | PMID: 10950058 |
Complete mutational screening of the cystic fibrosis transmembrane conductance regulator gene: cystic fibrosis mutations are not involved in healthy men with reduced sperm quality. | Pallares-Ruiz N | Human reproduction (Oxford, England) | 1999 | PMID: 10601093 |
Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. | Dörk T | Human genetics | 1997 | PMID: 9272157 |
Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. | Kerem BS | Proceedings of the National Academy of Sciences of the United States of America | 1990 | PMID: 2236053 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs1800095 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.