ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3877G>A (p.Val1293Ile)
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.3877G>A (p.Val1293Ile)
Variation ID: 552594 Accession: VCV000552594.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117652845 (GRCh38) [ NCBI UCSC ] 7: 117292899 (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 Aug 5, 2018 Oct 8, 2024 Dec 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3877G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Val1293Ile missense NC_000007.14:g.117652845G>A NC_000007.13:g.117292899G>A NG_016465.4:g.192062G>A LRG_663:g.192062G>A LRG_663t1:c.3877G>A LRG_663p1:p.Val1293Ile - Protein change
- V1293I
- Other names
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- Canonical SPDI
- NC_000007.14:117652844: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
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 |
3816 | 5183 |
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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Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Aug 31, 2022 | RCV000667886.10 | |
CFTR-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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May 24, 2018 | RCV001835084.1 |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 8, 2021 | RCV002477491.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 2, 2023 | RCV003403550.1 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV003478392.8 |
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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Uncertain significance
(Dec 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004699819.7
First in ClinVar: Mar 10, 2024 Last updated: Oct 08, 2024 |
Comment:
CFTR: PM2, PM5:Supporting
Number of individuals with the variant: 1
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Uncertain significance
(Aug 31, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001421825.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1293 of the CFTR protein (p.Val1293Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1293 of the CFTR protein (p.Val1293Ile). This variant is present in population databases (rs769931559, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 12815607, 28040058). ClinVar contains an entry for this variant (Variation ID: 552594). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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
(Sep 05, 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: SCV002027522.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Uncertain significance
(Jul 08, 2021)
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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: SCV002780958.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Aug 20, 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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Ambry Genetics
Accession: SCV002624882.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.V1293I variant (also known as c.3877G>A), located in coding exon 24 of the CFTR gene, results from a G to A substitution at nucleotide … (more)
The p.V1293I variant (also known as c.3877G>A), located in coding exon 24 of the CFTR gene, results from a G to A substitution at nucleotide position 3877. The valine at codon 1293 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in a cystic fibrosis cohort with no second CFTR varaint and in a control sample (El-Seedy A et al. Cell. Mol. Biol. (Noisy-le-grand), 2016 Nov;62:21-28; Le Maréchal C et al. Hum. Genet., 2001 Apr;108:290-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Oct 02, 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: SCV004122651.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: CFTR c.3877G>A (p.Val1293Ile) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. … (more)
Variant summary: CFTR c.3877G>A (p.Val1293Ile) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250000 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3877G>A has been reported in the literature in at least one individual affected with Cystic Fibrosis (e.g., El-Seedy_2016), however without strong evidence for causality. This report therefore does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function (e.g., Bihler_2023, no PMID). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 28040058, 11379874, 20974851, 15536480, 16251901, 17244607). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jun 23, 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: SCV004221695.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The CFTR c.3877G>A (p.Val1293Ile) variant has been reported in the published literature in an individual with cystic fibrosis (PMID: 28040058 (2016)) and in healthy unaffected … (more)
The CFTR c.3877G>A (p.Val1293Ile) variant has been reported in the published literature in an individual with cystic fibrosis (PMID: 28040058 (2016)) and in healthy unaffected individuals (PMID: 16251901 (2006), 11379874 (2001)). The frequency of this variant in the general population, 0.000036 (4/111742 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jun 27, 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: SCV000792398.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(May 24, 2018)
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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: SCV002075901.1
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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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations in North Egyptian population: implications for the genetic diagnosis in Egypt. | El-Seedy A | Cellular and molecular biology (Noisy-le-Grand, France) | 2016 | PMID: 28040058 |
Modulation of cystic fibrosis transmembrane conductance regulator (CFTR) activity and genistein binding by cytosolic pH. | Melani R | The Journal of biological chemistry | 2010 | PMID: 20974851 |
Functional analysis of mutations in the putative binding site for cystic fibrosis transmembrane conductance regulator potentiators. Interaction between activation and inhibition. | Zegarra-Moran O | The Journal of biological chemistry | 2007 | PMID: 17244607 |
Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations. | Pompei F | European journal of human genetics : EJHG | 2006 | PMID: 16251901 |
A large-scale study of the random variability of a coding sequence: a study on the CFTR gene. | Modiano G | European journal of human genetics : EJHG | 2005 | PMID: 15536480 |
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 |
Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. | Le Maréchal C | Human genetics | 2001 | PMID: 11379874 |
Text-mined citations for rs769931559 ...
HelpRecord last updated Oct 08, 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.