CFTR c.3794G>T has been previously identified in individuals with features of cystic fibrosis and has been reported in ClinVar. It is absent from a large population dataset. Three bioinformatic tools queried predict that this substitution would probably be damaging, and the glycine residue at this position is evolutionarily conserved across all species assessed. Due to lack of functional evidence that this variant is deleterious, we consider its the clinical significance to be uncertain at this time.
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3794G>T (p.Gly1265Val)
Germline
Classification
Help
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.
(7)
Help
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.
Uncertain significance
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.3794G>T (p.Gly1265Val)
Variation ID: 502505 Accession: VCV000502505.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117642514 (GRCh38) [ NCBI UCSC ] 7: 117282568 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 2, 2018 Jul 7, 2024 Mar 27, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.3794G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Gly1265Val missense NC_000007.14:g.117642514G>T NC_000007.13:g.117282568G>T NG_016465.4:g.181731G>T LRG_663:g.181731G>T LRG_663t1:c.3794G>T LRG_663p1:p.Gly1265Val - Protein change
- G1265V
- Other names
- -
- Canonical SPDI
- NC_000007.14:117642513:G: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
Help
The frequency of the allele represented by this VCV record.
- -
- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| CFTR | - | - |
GRCh38 GRCh37 |
3826 | 5201 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 8, 2017 | RCV000594452.4 | |
| Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 18, 2022 | RCV000664824.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 27, 2024 | RCV004526715.3 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 04, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000788842.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Uncertain significance
(Jun 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000709270.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Uncertain significance
(Nov 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: yes
Allele origin:
unknown
|
Mendelics
Accession: SCV000886386.2
First in ClinVar: Aug 05, 2018 Last updated: Dec 11, 2022 |
|
|
|
Uncertain significance
(May 22, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425411.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Comment:
CFTR c.3794G>T has been previously identified in individuals with features of cystic fibrosis and has been reported in ClinVar. It is absent from a large … (more)
CFTR c.3794G>T has been previously identified in individuals with features of cystic fibrosis and has been reported in ClinVar. It is absent from a large population dataset. Three bioinformatic tools queried predict that this substitution would probably be damaging, and the glycine residue at this position is evolutionarily conserved across all species assessed. Due to lack of functional evidence that this variant is deleterious, we consider its the clinical significance to be uncertain at this time. (less)
|
|
|
Uncertain significance
(Sep 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002027519.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
|
|
|
Uncertain significance
(Oct 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002930594.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1265 of the CFTR protein (p.Gly1265Val). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1265 of the CFTR protein (p.Gly1265Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 26708955). ClinVar contains an entry for this variant (Variation ID: 502505). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. 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
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039018.3
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: CFTR c.3794G>T (p.Gly1265Val) results in a non-conservative amino acid change located in the 2nd ATP-binding domain (IPR003439) of the encoded protein sequence. Five … (more)
Variant summary: CFTR c.3794G>T (p.Gly1265Val) results in a non-conservative amino acid change located in the 2nd ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251024 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3794G>T has been reported in the literature in cohorts of individuals affected with Cystic Fibrosis (e.g. Schrijver_2016, Da Silva Filho_2020, Raraigh_2022), however no geno- and phenotype details were specified in these patients. These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated significantly reduced expression levels and Cl- channel function for the variant protein (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 26708955, 34782259, 32819855, 38388235). ClinVar contains an entry for this variant (Variation ID: 502505). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
|
Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1265 of the CFTR protein (p.Gly1265Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 26708955). ClinVar contains an entry for this variant (Variation ID: 502505). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. 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.
Comment:
Variant summary: CFTR c.3794G>T (p.Gly1265Val) results in a non-conservative amino acid change located in the 2nd ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251024 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3794G>T has been reported in the literature in cohorts of individuals affected with Cystic Fibrosis (e.g. Schrijver_2016, Da Silva Filho_2020, Raraigh_2022), however no geno- and phenotype details were specified in these patients. These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated significantly reduced expression levels and Cl- channel function for the variant protein (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 26708955, 34782259, 32819855, 38388235). ClinVar contains an entry for this variant (Variation ID: 502505). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
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. |
Comment:
CFTR c.3794G>T has been previously identified in individuals with features of cystic fibrosis and has been reported in ClinVar. It is absent from a large population dataset. Three bioinformatic tools queried predict that this substitution would probably be damaging, and the glycine residue at this position is evolutionarily conserved across all species assessed. Due to lack of functional evidence that this variant is deleterious, we consider its the clinical significance to be uncertain at this time.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1265 of the CFTR protein (p.Gly1265Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 26708955). ClinVar contains an entry for this variant (Variation ID: 502505). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. 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.
Comment:
Variant summary: CFTR c.3794G>T (p.Gly1265Val) results in a non-conservative amino acid change located in the 2nd ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251024 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3794G>T has been reported in the literature in cohorts of individuals affected with Cystic Fibrosis (e.g. Schrijver_2016, Da Silva Filho_2020, Raraigh_2022), however no geno- and phenotype details were specified in these patients. These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated significantly reduced expression levels and Cl- channel function for the variant protein (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 26708955, 34782259, 32819855, 38388235). ClinVar contains an entry for this variant (Variation ID: 502505). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| In vitro modulator responsiveness of 655 CFTR variants found in people with cystic fibrosis. | Bihler H | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2024 | PMID: 38388235 |
| Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. | Raraigh KS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2022 | PMID: 34782259 |
| Extensive CFTR sequencing through NGS in Brazilian individuals with cystic fibrosis: unravelling regional discrepancies in the country. | da Silva Filho LVRF | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2021 | PMID: 32819855 |
| The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. | Schrijver I | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26708955 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
Text-mined citations for rs1554395370 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.