ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3469-20T>C
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3469-20T>C
Variation ID: 7228 Accession: VCV000007228.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117627502 (GRCh38) [ NCBI UCSC ] 7: 117267556 (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 17, 2018 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3469-20T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000007.14:g.117627502T>C NC_000007.13:g.117267556T>C NG_016465.4:g.166719T>C LRG_663:g.166719T>C LRG_663t1:c.3469-20T>C - Protein change
- Other names
- 3601, T-C, -20
- Canonical SPDI
- NC_000007.14:117627501:T:C
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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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0.00759 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00148
Exome Aggregation Consortium (ExAC) 0.00188
1000 Genomes Project 0.00759
1000 Genomes Project 30x 0.00765
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
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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 |
3689 | 5008 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000007649.27 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2022 | RCV000595140.17 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Apr 26, 2023 | RCV001810837.16 | |
Benign (1) |
criteria provided, single submitter
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Mar 1, 2021 | RCV002255258.8 |
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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Benign
(Jun 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000709545.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(-)
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criteria provided, single submitter
Method: research
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Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435188.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The heterozygous c.3469-20T>C variant in CFTR has been reported in at least 3 individuals with cystic fibrosis without another variant identified in the gene (PMID: … (more)
The heterozygous c.3469-20T>C variant in CFTR has been reported in at least 3 individuals with cystic fibrosis without another variant identified in the gene (PMID: 10869121, 20551465, 21520337), and has been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive cystic fibrosis. (less)
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Benign
(Mar 01, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529714.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Oct 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696971.4
First in ClinVar: Mar 17, 2018 Last updated: Nov 19, 2022 |
Comment:
Variant summary: CFTR c.3469-20T>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered … (more)
Variant summary: CFTR c.3469-20T>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 250478 control chromosomes, predominantly at a frequency of 0.012 within the South Asian subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Cystic Fibrosis (0.012 vs 0.013), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant, c.3469-20T>C, has been reported in the literature in individuals affected with Cystic Fibrosis and idiopathic chronic pancreatitis, without strong evidence for causality (e.g. Kabra_2000, Midha_2010, Steiner_2011, Claustres_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The variant was also found in a French CF patient as a complex allele in cis with a pathogenic CFTR variant c.3197G>A (p.Arg1066His), suggesting a possibly non-pathogenic role for the variant of interest (Claustres_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The majority classified the variant as either benign (n=3) or likely benign (n=1), and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Benign
(Mar 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159203.4
First in ClinVar: Feb 09, 2020 Last updated: Mar 04, 2023 |
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Benign
(Aug 22, 2023)
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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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Mendelics
Accession: SCV001137493.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Likely benign
(Apr 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221689.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
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Benign
(Jan 31, 2024)
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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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Invitae
Accession: SCV001731520.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 28, 2024 |
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Benign
(Dec 13, 2015)
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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: SCV002618779.2
First in ClinVar: Nov 29, 2022 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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Pathogenic
(Jul 17, 2000)
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no assertion criteria provided
Method: literature only
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CYSTIC FIBROSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027850.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 12, 2018 |
Comment on evidence:
In 2 Indian patients with cystic fibrosis (CF; 219700), Kabra et al. (2000) identified a T-to-C change at position -20 from nucleotide 3601 of the … (more)
In 2 Indian patients with cystic fibrosis (CF; 219700), Kabra et al. (2000) identified a T-to-C change at position -20 from nucleotide 3601 of the CFTR gene. (less)
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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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Genetic variants in children with chronic respiratory diseases. | Alsamri MT | Pediatric pulmonology | 2020 | PMID: 32662942 |
Guidelines for the clinical management and follow-up of infants with inconclusive cystic fibrosis diagnosis through newborn screening. | Sermet-Gaudelus I | Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | 2017 | PMID: 29174009 |
CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. | Claustres M | Human mutation | 2017 | PMID: 28603918 |
Analysis of protein-coding genetic variation in 60,706 humans. | Lek M | Nature | 2016 | PMID: 27535533 |
Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk. | Lim RM | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 25880441 |
Elevated sweat chloride levels due to arsenic toxicity. | Mazumdar M | The New England journal of medicine | 2015 | PMID: 25651269 |
Cystic fibrosis in India: a systematic review. | Ashavaid TF | The Journal of the Association of Physicians of India | 2012 | PMID: 23405520 |
Association of CFTR gene mutation with bronchial asthma. | Maurya N | The Indian journal of medical research | 2012 | PMID: 22664493 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
Idiopathic chronic pancreatitis in India: phenotypic characterisation and strong genetic susceptibility due to SPINK1 and CFTR gene mutations. | Midha S | Gut | 2010 | PMID: 20551465 |
Cystic fibrosis in India. | Kabra SK | Pediatric pulmonology | 2007 | PMID: 17968991 |
Is the spectrum of mutations in Indian patients with cystic fibrosis different? | Kabra M | American journal of medical genetics | 2000 | PMID: 10869121 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs373002889 ...
HelpRecord last updated May 01, 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.