ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3276C>A (p.Tyr1092Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3276C>A (p.Tyr1092Ter)
Variation ID: 38728 Accession: VCV000038728.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117611717 (GRCh38) [ NCBI UCSC ] 7: 117251771 (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 Dec 22, 2015 Jun 17, 2024 Mar 17, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3276C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Tyr1092Ter nonsense NC_000007.14:g.117611717C>A NC_000007.13:g.117251771C>A NG_016465.4:g.150934C>A NG_056128.2:g.4771C>A LRG_663:g.150934C>A LRG_663t1:c.3276C>A LRG_663p1:p.Tyr1092Ter - Protein change
- Y1092*
- Other names
- Y1092X C->A
- Canonical SPDI
- NC_000007.14:117611716:C: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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 |
3806 | 5170 | |
LOC111674472 | - | - | - | GRCh38 | - | 398 |
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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Pathogenic (8) |
reviewed by expert panel
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Mar 17, 2017 | RCV000056379.20 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2023 | RCV000522700.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2018 | RCV000781257.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2022 | RCV000763157.3 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004305.1 | |
CFTR-related disorder
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Pathogenic (2) |
criteria provided, single submitter
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Mar 2, 2024 | RCV001831621.3 |
Pathogenic (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV003473243.2 |
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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Pathogenic
(Mar 17, 2017)
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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
Study: CFTR2
Accession: SCV000071565.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018 |
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Pathogenic
(Aug 14, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000854906.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Feb 28, 2018)
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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: SCV000616674.2
First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019 |
Comment:
The Y1092X pathogenic variant in the CFTR gene has been reported previously as a cystic fibrosis-causing variant, accounting for approximately 0.2% of all cystic fibrosis … (more)
The Y1092X pathogenic variant in the CFTR gene has been reported previously as a cystic fibrosis-causing variant, accounting for approximately 0.2% of all cystic fibrosis mutant alleles (Tsui, 1992; Sosnay et al., 2013). The Y1092X variant has also been implicated in chronic pancreatitis and pancreatic insufficiency (Ockenga et al., 2000; Ooi and Durie, 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y1092X variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). We interpret Y1092X as a pathogenic variant. (less)
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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: SCV001163182.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169281.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Pathogenic
(Dec 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194063.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000492.3(CFTR):c.3276C>A(Y1092*) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID … (more)
NM_000492.3(CFTR):c.3276C>A(Y1092*) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 18456578, 1284534 and 23974870. Classification of NM_000492.3(CFTR):c.3276C>A(Y1092*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446980.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Azoospermia (present)
Sex: male
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Pathogenic
(Jun 03, 2021)
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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: SCV001711960.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
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Pathogenic
(Jan 18, 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: SCV001584104.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr1092*) in the CFTR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr1092*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with cystic fibrosis and chronic pancreatitis. A second, pathogenic, CFTR variant was not reported in this individual (PMID: 10950058, 12815607, 15480987, 18456578, 21416780, 23974870, 24586523, 25910067). ClinVar contains an entry for this variant (Variation ID: 38728). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 28, 2024)
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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: SCV004213375.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Dec 13, 2018)
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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: SCV000919166.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: The variant CFTR c.3276C>A (p.Tyr1092X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of … (more)
Variant summary: The variant CFTR c.3276C>A (p.Tyr1092X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 245972 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Bozon_1994, DeBraekeleer_1998, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Mendelics
Accession: SCV000886190.2
First in ClinVar: Jan 06, 2018 Last updated: Dec 11, 2022 |
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Pathogenic
(Jan 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pancreatitis
Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893744.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 07, 2023)
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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: SCV004563283.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.3276C>A; p.Tyr1092Ter variant (rs121908761) has been reported in the medical literature in several individuals with pancreatic insufficient cystic fibrosis (Castellani 2008, De Braekeleer … (more)
The CFTR c.3276C>A; p.Tyr1092Ter variant (rs121908761) has been reported in the medical literature in several individuals with pancreatic insufficient cystic fibrosis (Castellani 2008, De Braekeleer 1998, Sosnay 2013). The variant is reported in ClinVar (Variation ID: 38728) and is reported in the general population with an overall allele frequency of 0.0018% (5/282,504 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Castellani C et al. Consensus on the Use and Interpretation of Cystic Fibrosis Mutation Analysis in Clinical Practice. J Cyst Fibros. 2008 May;7(3):179-96. PMID: 18456578. De Braekeleer M et al. Phenotypic Variability in Five Cystic Fibrosis Patients Compound Heterozygous for the Y1092X Mutation. Hum Hered. May-Jun 1998;48(3):158-62. PMID: 9618063. Sosnay PR et al. Defining the Disease Liability of Variants in the Cystic Fibrosis Transmembrane Conductance Regulator Gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. (less)
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Pathogenic
(Mar 02, 2024)
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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: SCV004727965.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CFTR c.3276C>A variant is predicted to result in premature protein termination (p.Tyr1092*). This variant has been reported in the compound heterozygous state in multiple … (more)
The CFTR c.3276C>A variant is predicted to result in premature protein termination (p.Tyr1092*). This variant has been reported in the compound heterozygous state in multiple individuals with cystic fibrosis (Bozon et al. 1994. PubMed ID: 7517268; Scotet et al. 2003. PubMed ID: 12815607; Sosnay et al. 2013. PubMed ID: 23974870; Ziętkiewicz et al. 2014. PubMed ID: 24586523; Lucarelli et al. 2015. PubMed ID: 25910067; Raraigh et al. 2022. PubMed ID: 34782259) and has been observed to co-segregate with disease in a large French Canadian family (De Braekeleer et al. 1998. PubMed ID: 9618063). It has also been reported as a single heterozygous variant in a patient with chronic pancreatitis (Ockenga et al. 2000. PubMed ID: 10950058). A different nucleotide substitution with the same predicted effect (c.3276C>G, p.Tyr1092*) has also been reported in multiple individuals with cystic fibrosis (Schrijver et al. 2005. PubMed ID: 16049310; Raraigh et al. 2022. PubMed ID: 34782259) and an absence of chloride channel function has been noted in in vitro studies of biopsied tissue samples and primary cell cultures from patients heterozygous for both the p.Phe508del and p.Tyr1092* variants (Hirtz et al. 2004. PubMed ID: 15480987; Awatade et al. 2015. PubMed ID: 26137539). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Taken together, this variant is interpreted as pathogenic. (less)
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Pathogenic
(May 09, 2021)
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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: SCV002612074.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Y1092* pathogenic mutation (also known as c.3276C>A), located in coding exon 20 of the CFTR gene, results from a C to A substitution at … (more)
The p.Y1092* pathogenic mutation (also known as c.3276C>A), located in coding exon 20 of the CFTR gene, results from a C to A substitution at nucleotide position 3276. This changes the amino acid from a tyrosine to a stop codon within coding exon 20. This pathogenic mutation was first described in an individual with pancreatic insufficient cystic fibrosis in conjunction with p.F508del (Bozon D et al. Hum. Mutat., 1994;3:330-2). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 01, 1993)
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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: SCV000143751.1
First in ClinVar: Dec 22, 2015 Last updated: Dec 22, 2015 |
Comment on evidence:
In a systematic study of 133 CF (219700) individuals in northern Italy, Gasparini et al. (1993) found a point mutation creating a stop codon in … (more)
In a systematic study of 133 CF (219700) individuals in northern Italy, Gasparini et al. (1993) found a point mutation creating a stop codon in place of tyrosine-1092. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739694.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955636.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967151.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083621.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 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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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 |
CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients. | Ziętkiewicz E | PloS one | 2014 | PMID: 24586523 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. | Chávez-Saldaña M | Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion | 2010 | PMID: 21416780 |
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. | Castellani C | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2008 | PMID: 18456578 |
CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. | Hirtz S | Gastroenterology | 2004 | PMID: 15480987 |
Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland. | Scotet V | Human mutation | 2003 | PMID: 12815607 |
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 |
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. | Cohn JA | The New England journal of medicine | 1998 | PMID: 9725922 |
Phenotypic variability in five cystic fibrosis patients compound heterozygous for the Y1092X mutation. | De Braekeleer M | Human heredity | 1998 | PMID: 9618063 |
Identification of four new mutations in the cystic fibrosis transmembrane conductance regulator gene: I148T, L1077P, Y1092X, 2183AA-->G. | Bozon D | Human mutation | 1994 | PMID: 7517268 |
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR. | Yang Y | Human molecular genetics | 1993 | PMID: 7691345 |
Screening of 62 mutations in a cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes. | Gasparini P | Human mutation | 1993 | PMID: 7504969 |
Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium. | Tsui LC | Human mutation | 1992 | PMID: 1284534 |
A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. | Cutting GR | Nature | 1990 | PMID: 1695717 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
https://cftr2.org | - | - | - | - |
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Text-mined citations for rs121908761 ...
HelpRecord last updated Sep 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.