ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.859A>T (p.Asn287Tyr)
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.
Likely pathogenic(3); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.859A>T (p.Asn287Tyr)
Variation ID: 54069 Accession: VCV000054069.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117536663 (GRCh38) [ NCBI UCSC ] 7: 117176717 (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 Jan 25, 2018 Jun 17, 2024 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.859A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Asn287Tyr missense NC_000007.14:g.117536663A>T NC_000007.13:g.117176717A>T NG_016465.4:g.75880A>T LRG_663:g.75880A>T LRG_663t1:c.859A>T LRG_663p1:p.Asn287Tyr P13569:p.Asn287Tyr - Protein change
- N287Y
- Other names
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- Canonical SPDI
- NC_000007.14:117536662:A: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00001
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
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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 |
3712 | 5035 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Nov 13, 2023 | RCV000577376.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV001004240.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 15, 2024 | RCV003474621.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 6, 2023 | RCV003478990.1 |
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
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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
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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 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: SCV001163116.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Uncertain significance
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001822024.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Likely pathogenic
(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: SCV002574061.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Comment:
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project … (more)
This variant was identified in 1 patient 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_MOD, PM2_SUP, PM3, PP3 (less)
Number of individuals with the variant: 1
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Uncertain significance
(Nov 14, 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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Invitae
Accession: SCV002307517.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 287 of the CFTR protein (p.Asn287Tyr). … (more)
This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 287 of the CFTR protein (p.Asn287Tyr). This variant is present in population databases (rs397508804, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9401006). ClinVar contains an entry for this variant (Variation ID: 54069). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 12529365). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Nov 13, 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: SCV002679925.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.N287Y variant (also known as c.859A>T), located in coding exon 7 of the CFTR gene, results from an A to T substitution at nucleotide … (more)
The p.N287Y variant (also known as c.859A>T), located in coding exon 7 of the CFTR gene, results from an A to T substitution at nucleotide position 859. The asparagine at codon 287 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration was identified with Delta F508 in an individual with a clinical diagnosis of cystic fibrosis (Shrimpton AE et al. Hum Mutat, 1997;10:436-42). In vitro studies showed CFTR protein harboring N287Y has normal maturation, cell surface targeting, and channel gating. However, this variant increased internalization of the protein, leading to reduced expression on the cell surface (Silvis MR et al. J Biol Chem, 2003 Mar;278:11554-60). Additionally, this alteration was identified in an individual diagnosed with idiopathic chronic pancreatitis (Chang MC et al. Clin Genet, 2007 Jun;71:530-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Jan 15, 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: SCV004213287.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Mar 15, 2017)
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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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Counsyl
Accession: SCV000788445.1
First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018 |
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Uncertain significance
(Nov 06, 2023)
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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: SCV000697049.2
First in ClinVar: Mar 17, 2018 Last updated: Jan 06, 2024 |
Comment:
Variant summary: CFTR c.859A>T (p.Asn287Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded … (more)
Variant summary: CFTR c.859A>T (p.Asn287Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 252260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.859A>T has been reported in the literature in the compound heterozygous state together with p.Phe508del in an individual with a mild form of Cystic Fibrosis (Shrimpton_1997) and in the heterozygous state in two individuals with with idiopathic chronic pancreatitis (Chang_2007). The variant has also been observed in 2 additional patients: one referred for genetic testing for chronic pancreatitis, and the other was asymptomatic but had a 1st cousin with CF (internal LCA data). Both patients also tested positive for c.2052dupA (p.Gln685ThrfsX4; phase is unknown), a mutation known to be associated with pancreatic insufficient CF. The UMD database also reported the variant of interest in one CF patient who had c.1521_1523delCTT (p.Phe508del) on the other allele and also carried c.2052dup (p.Gln685ThrfsX4; phase not specified), suggesting that c.859A>T (p.Asn287Tyr) may not be the cause of CF in this patient if the two pathogenic variants (i.e. p.Gln685ThrfsX4 and p.Phe508del) were in trans. It is possible that p.Gln685ThrfsX4 may be in cis with p.Asn287Tyr given these two relatively uncommon variants (p.Gln685ThrfsX4 has an allele frequency of 2/119584 in ExAC) were found together in 3 individuals and co-segregated together in one family (internal LCA data). At least one publication reports experimental evidence evaluating an impact on protein function (Silvis_2003). In these experiments, the variant did not exhibit a folding defect, as evidenced by similar maturation kinetics to the wild type CFTR protein. However, there was roughly 50% of the variant protein located at the plasma membrane at the steady state relative to wild type CFTR. Cholride transport was reduced in proportion to altered cell surface CFTR, but the single-channel properties of the variant were similar to those of the wild type. Biotinylation experiments showed that the variant protein was internalized approximately twice as fast as wild type CFTR, which is expected to alter its distribution between the plasma membrane and intracellular compartments, reducing its expression at the cell surface. The following publications have been ascertained in the context of this evaluation (PMID: 34740355, 17539902, 9401006, 12529365, 16339147, 25735457). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454033.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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CFTR-related disorders
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000679177.1
First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018 |
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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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Frequency of allele variations in the CFTR gene in a Mexican population. | Cantú-Reyna C | BMC medical genomics | 2021 | PMID: 34740355 |
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. | Ramalho AS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 25735457 |
Diagnostic problems in cystic fibrosis - specific characteristics of a group of infants and young children diagnosed positive through neonatal screening, in whom cystic fibrosis had not been diagnosed. | Woś H | Developmental period medicine | 2015 | PMID: 26003067 |
Cystic fibrosis genetics: from molecular understanding to clinical application. | Cutting GR | Nature reviews. Genetics | 2015 | PMID: 25404111 |
Cystic fibrosis: toward personalized therapies. | Ikpa PT | The international journal of biochemistry & cell biology | 2014 | PMID: 24561283 |
CFTR: folding, misfolding and correcting the ΔF508 conformational defect. | Lukacs GL | Trends in molecular medicine | 2012 | PMID: 22138491 |
The p.Arg258Gly mutation in intracellular loop 2 of CFTR is associated with CFTR-related disorders. | Masvidal L | Genetic testing and molecular biomarkers | 2009 | PMID: 19810821 |
Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. | Chang MC | Clinical genetics | 2007 | PMID: 17539902 |
Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. | Thelin WR | The Journal of clinical investigation | 2007 | PMID: 17235394 |
Endocytic trafficking of CFTR in health and disease. | Ameen N | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2007 | PMID: 17098482 |
Mutations in the amino terminus of the cystic fibrosis transmembrane conductance regulator enhance endocytosis. | Jurkuvenaite A | The Journal of biological chemistry | 2006 | PMID: 16339147 |
Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations. | Schrijver I | The Journal of molecular diagnostics : JMD | 2005 | PMID: 16049310 |
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Text-mined citations for rs397508804 ...
HelpRecord last updated Jun 23, 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.