ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.165-3C>T
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.165-3C>T
Variation ID: 53317 Accession: VCV000053317.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117509031 (GRCh38) [ NCBI UCSC ] 7: 117149085 (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 29, 2015 May 1, 2024 Jan 10, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.165-3C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000007.14:g.117509031C>T NC_000007.13:g.117149085C>T NG_016465.4:g.48248C>T NG_062452.1:g.669C>T LRG_663:g.48248C>T LRG_663t1:c.165-3C>T - Protein change
- Other names
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- Canonical SPDI
- NC_000007.14:117509030:C:T
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 | |
LOC113664106 | - | - | - | GRCh38 | - | 57 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (7) |
reviewed by expert panel
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Jan 10, 2020 | RCV000046385.25 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004227.8 | |
CFTR-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2015 | RCV001009538.8 |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2023 | RCV003233099.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 14, 2023 | RCV003473460.1 |
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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Uncertain significance
(Jan 10, 2020)
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reviewed by expert panel
Method: research
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR2
Accession: SCV000924237.2
First in ClinVar: Jun 17, 2019 Last updated: Oct 25, 2021 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163103.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Jul 01, 2015)
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criteria provided, single submitter
Method: curation
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cystic fibrosis
CFTR-related disorders
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169633.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
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Likely pathogenic
(Sep 17, 2014)
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criteria provided, single submitter
Method: literature only
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Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220698.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Sep 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213386.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Dec 21, 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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Invitae
Accession: SCV002267945.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 2 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. … (more)
This sequence change falls in intron 2 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs200337193, gnomAD 0.005%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 19833837). This variant is also known as 297-3C>T. ClinVar contains an entry for this variant (Variation ID: 53317). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3 and introduces a premature termination codon (PMID: 7518409). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Mar 29, 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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004808191.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(Oct 25, 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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Ambry Genetics
Accession: SCV001173070.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.165-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 3 in the CFTR gene. This variant was … (more)
The c.165-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 3 in the CFTR gene. This variant was detected in conjunction with a second CFTR alteration in a 44-year-old woman with cystic fibrosis who presented with elevated sweat chloride levels, pulmonary symptoms, and pancreatic sufficiency; however, the pathogenicity of the second alteration was uncertain (Bienvenu T et al. Hum. Genet., 1994 Jul;94:65-8). This alteration was also reported in a fetus with meconium ileus who had p.F508del (Oca F et al. Clin. Chem., 2009 Dec;55:2214-7). In addition, functional studies showed that the variant results in skipping of exon 3 (Bienvenu T et al. Hum. Genet., 1994 Jul;94:65-8; Leman R et al. Nucleic Acids Res, 2018 Sep;46:7913-7923; Joynt AT et al. PLoS Genet, 2020 Oct;16:e1009100). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Jun 09, 2023)
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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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GeneDx
Accession: SCV003930979.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Classified as a variant of uncertain significance in a well curated database (CFTR2); Published functional studies demonstrate abnormal splicing resulting in aberrant transcript lacking exon … (more)
Classified as a variant of uncertain significance in a well curated database (CFTR2); Published functional studies demonstrate abnormal splicing resulting in aberrant transcript lacking exon 3 as well as some residual full-length transcript (Leman et al., 2018; Joynt et al., 2020); A different variant at this position, c.165-3C>A (reported as 297-3C>A), has been identified in an individual with clinical features of cystic fibrosis who also carried a pathogenic CFTR variant (Strandvik et al., 2001); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as 297-3C>T; This variant is associated with the following publications: (PMID: 28603918, 7550227, 7518409, 29750258, 16617247, 31036917, 8947061, 25087612, 19833837, 26574590, 32126153, 10923036, 32256364, 10982968, 34782259, 11788090, 34996830, 33085659) (less)
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Likely pathogenic
(Dec 14, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338125.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 04, 2024 |
Comment:
Variant summary: CFTR c.165-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: CFTR c.165-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3 acceptor site. Several functional studies report this variant affects mRNA splicing and results in exon 3 skipping (Bienvenu_1994, Leman_2018, Joynt_2020). The variant allele was found at a frequency of 2.4e-05 in 250574 control chromosomes (gnomAD). c.165-3C>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Bienvenu_1994, Oca_2009, Kharrazi_2015). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 19833837, 7550227, 10982968, 7518409, 8947061, 25087612, 26574590, 29750258, 16617247, 32126153, 31036917, 32256364, 33085659, 34996830, 34196078). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1) and likely pathogenic (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV002583265.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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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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C FTR variants are associated with chronic bronchitis in smokers. | Saferali A | The European respiratory journal | 2022 | PMID: 34996830 |
Elucidating clinical phenotypic variability associated with the polyT tract and TG repeats in CFTR. | Nykamp K | Human mutation | 2021 | PMID: 34196078 |
Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies. | Joynt AT | PLoS genetics | 2020 | PMID: 33085659 |
Functional and Pharmacological Characterization of the Rare CFTR Mutation W361R. | Billet A | Frontiers in pharmacology | 2020 | PMID: 32256364 |
AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides. | Wimmer K | Human mutation | 2020 | PMID: 32126153 |
Sequencing as a first-line methodology for cystic fibrosis carrier screening. | Beauchamp KA | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31036917 |
Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort. | Leman R | Nucleic acids research | 2018 | PMID: 29750258 |
Newborn Screening for Cystic Fibrosis in California. | Kharrazi M | Pediatrics | 2015 | PMID: 26574590 |
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 |
Amniotic fluid digestive enzyme analysis is useful for identifying CFTR gene mutations of unclear significance. | Oca F | Clinical chemistry | 2009 | PMID: 19833837 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Cystic Fibrosis testing among Arab-Americans. | Wei S | Genetics in medicine : official journal of the American College of Medical Genetics | 2006 | PMID: 16617247 |
Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. | Strandvik B | Genetic testing | 2001 | PMID: 11788090 |
Mutation analysis of the cystic fibrosis and cationic trypsinogen genes in patients with alcohol-related pancreatitis. | Monaghan KG | American journal of medical genetics | 2000 | PMID: 10982968 |
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. | Claustres M | Human mutation | 2000 | PMID: 10923036 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients. | Hubert D | The European respiratory journal | 1996 | PMID: 8947061 |
Mutation heterogeneity of cystic fibrosis in France: screening by denaturing gradient gel electrophoresis using psoralen-modified oligonucleotide. | Bienvenu T | Human mutation | 1995 | PMID: 7550227 |
Unexpected inactivation of acceptor consensus splice sequence by a -3 C to T transition in intron 2 of the CFTR gene. | Bienvenu T | Human genetics | 1994 | PMID: 7518409 |
https://cftr2.org | - | - | - | - |
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Text-mined citations for rs200337193 ...
HelpRecord last updated Jun 02, 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.