The CFTR variant c.-812T>G has been reported in the published literature in individuals affected with CF (PMIDs: 30296588 (2018), 23470247 (2013), 7540587 (1995)), CBAVD (PMID: 23470247 (2013)), and other CF-related disorders (PMIDs: 25797027 (2015), 18703788 (2008)). Functional studies show conflicting data, and the variant may affect CFTR promoter activity (PMIDs: 30296588 (2018), 25797027 (2015), 23470247 (2013), 7540587 (1995)). The frequency of this variant in the general population, 0.0052 (81/15406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.-812T>G
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.
(8)
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.
Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(3); Likely benign(1)
Uncertain significance(3); Benign(3); Likely benign(1)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.-812T>G
Variation ID: 51029 Accession: VCV000051029.37
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117479283 (GRCh38) [ NCBI UCSC ] 7: 117119337 (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 Jul 1, 2016 Oct 20, 2024 Jun 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.-812T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000007.14:g.117479283T>G NC_000007.13:g.117119337T>G NG_016465.4:g.18500T>G NG_056120.2:g.3313T>G LRG_663:g.18500T>G LRG_663t1:c.-812T>G - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000007.14:117479282:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00120 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00120
1000 Genomes Project 30x 0.00156
The Genome Aggregation Database (gnomAD) 0.00375
Trans-Omics for Precision Medicine (TOPMed) 0.00390
- 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 |
3832 | 5210 | |
| LOC111674463 | - | - | - | GRCh38 | - | 79 |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Sep 21, 2023 | RCV000043698.17 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 18, 2017 | RCV000507401.7 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jun 1, 2024 | RCV001281708.27 |
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
(Dec 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579839.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4_MOD, PM3, PM2_SUP
|
Number of individuals with the variant: 3
Sex: female
|
|
|
Uncertain significance
(Feb 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601133.5
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
Comment:
The CFTR variant c.-812T>G has been reported in the published literature in individuals affected with CF (PMIDs: 30296588 (2018), 23470247 (2013), 7540587 (1995)), CBAVD (PMID: … (more)
The CFTR variant c.-812T>G has been reported in the published literature in individuals affected with CF (PMIDs: 30296588 (2018), 23470247 (2013), 7540587 (1995)), CBAVD (PMID: 23470247 (2013)), and other CF-related disorders (PMIDs: 25797027 (2015), 18703788 (2008)). Functional studies show conflicting data, and the variant may affect CFTR promoter activity (PMIDs: 30296588 (2018), 25797027 (2015), 23470247 (2013), 7540587 (1995)). The frequency of this variant in the general population, 0.0052 (81/15406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Nov 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799887.3
First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.-812T>G variant (rs181008242) is reported in the literature in individuals affected with CFTR-related disorders such as pancreatitis or congenital bilateral absence of the … (more)
The CFTR c.-812T>G variant (rs181008242) is reported in the literature in individuals affected with CFTR-related disorders such as pancreatitis or congenital bilateral absence of the vas deferens (Giordano 2013, Mak 1999, Wilschanski 2006). This variant is also reported in ClinVar (Variation ID: 51029), and is found in the general population with an overall allele frequency of 0.34% (108/31356 alleles) in the Genome Aggregation Database. This variant occurs in the upstream promoter region at a nucleotide that is weakly conserved, but in vitro functional assays are conflicting for the effects on transcription and transcription factor binding (Bergougnoux 2015, Giordano 2013, Kerschner 2019). While this variant is not associated with classic cystic fibrosis, the clinical significance for CFTR-related disorders is uncertain. References: Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015 Sep;14(5):646-53. PMID: 25797027. Giordano S et al. Molecular and functional analysis of the large 5' promoter region of CFTR gene revealed pathogenic mutations in CF and CFTR-related disorders. J Mol Diagn. 2013 May;15(3):331-40. PMID: 23470247. Kerschner JL et al. Screening for Regulatory Variants in 460 kb Encompassing the CFTR Locus in Cystic Fibrosis Patients. J Mol Diagn. 2019 Jan;21(1):70-80. PMID: 30296588. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999 Jun 16;281(23):2217-24. PMID: 10376575. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. PMID: 16840743. (less)
|
|
|
Benign
(Feb 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002678958.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Benign
(Jun 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563974.16
First in ClinVar: Aug 23, 2022 Last updated: Oct 20, 2024 |
Comment:
CFTR: BS1, BS2
Number of individuals with the variant: 20
|
|
|
Likely benign
(Jan 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000705550.2
First in ClinVar: Mar 30, 2018 Last updated: Mar 30, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Benign
(Sep 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000071711.9
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(Jun 15, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463999.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
The CFTR c.-812T>G variant (rs181008242) is reported in the literature in individuals affected with CFTR-related disorders such as pancreatitis or congenital bilateral absence of the vas deferens (Giordano 2013, Mak 1999, Wilschanski 2006). This variant is also reported in ClinVar (Variation ID: 51029), and is found in the general population with an overall allele frequency of 0.34% (108/31356 alleles) in the Genome Aggregation Database. This variant occurs in the upstream promoter region at a nucleotide that is weakly conserved, but in vitro functional assays are conflicting for the effects on transcription and transcription factor binding (Bergougnoux 2015, Giordano 2013, Kerschner 2019). While this variant is not associated with classic cystic fibrosis, the clinical significance for CFTR-related disorders is uncertain. References: Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015 Sep;14(5):646-53. PMID: 25797027. Giordano S et al. Molecular and functional analysis of the large 5' promoter region of CFTR gene revealed pathogenic mutations in CF and CFTR-related disorders. J Mol Diagn. 2013 May;15(3):331-40. PMID: 23470247. Kerschner JL et al. Screening for Regulatory Variants in 460 kb Encompassing the CFTR Locus in Cystic Fibrosis Patients. J Mol Diagn. 2019 Jan;21(1):70-80. PMID: 30296588. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999 Jun 16;281(23):2217-24. PMID: 10376575. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. PMID: 16840743.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
CFTR: BS1, BS2
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:
The CFTR variant c.-812T>G has been reported in the published literature in individuals affected with CF (PMIDs: 30296588 (2018), 23470247 (2013), 7540587 (1995)), CBAVD (PMID: 23470247 (2013)), and other CF-related disorders (PMIDs: 25797027 (2015), 18703788 (2008)). Functional studies show conflicting data, and the variant may affect CFTR promoter activity (PMIDs: 30296588 (2018), 25797027 (2015), 23470247 (2013), 7540587 (1995)). The frequency of this variant in the general population, 0.0052 (81/15406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The CFTR c.-812T>G variant (rs181008242) is reported in the literature in individuals affected with CFTR-related disorders such as pancreatitis or congenital bilateral absence of the vas deferens (Giordano 2013, Mak 1999, Wilschanski 2006). This variant is also reported in ClinVar (Variation ID: 51029), and is found in the general population with an overall allele frequency of 0.34% (108/31356 alleles) in the Genome Aggregation Database. This variant occurs in the upstream promoter region at a nucleotide that is weakly conserved, but in vitro functional assays are conflicting for the effects on transcription and transcription factor binding (Bergougnoux 2015, Giordano 2013, Kerschner 2019). While this variant is not associated with classic cystic fibrosis, the clinical significance for CFTR-related disorders is uncertain. References: Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015 Sep;14(5):646-53. PMID: 25797027. Giordano S et al. Molecular and functional analysis of the large 5' promoter region of CFTR gene revealed pathogenic mutations in CF and CFTR-related disorders. J Mol Diagn. 2013 May;15(3):331-40. PMID: 23470247. Kerschner JL et al. Screening for Regulatory Variants in 460 kb Encompassing the CFTR Locus in Cystic Fibrosis Patients. J Mol Diagn. 2019 Jan;21(1):70-80. PMID: 30296588. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999 Jun 16;281(23):2217-24. PMID: 10376575. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. PMID: 16840743.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
CFTR: BS1, BS2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Screening for Regulatory Variants in 460 kb Encompassing the CFTR Locus in Cystic Fibrosis Patients. | Kerschner JL | The Journal of molecular diagnostics : JMD | 2019 | PMID: 30296588 |
| Next-Generation Molecular Testing of Newborn Dried Blood Spots for Cystic Fibrosis. | Lefterova MI | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26847993 |
| Should diffuse bronchiectasis still be considered a CFTR-related disorder? | Bergougnoux A | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2015 | PMID: 25797027 |
| Molecular and functional analysis of the large 5' promoter region of CFTR gene revealed pathogenic mutations in CF and CFTR-related disorders. | Giordano S | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23470247 |
| Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? | Ooi CY | Thorax | 2012 | PMID: 22504961 |
| Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome. | Kim RD | American journal of respiratory and critical care medicine | 2008 | PMID: 18703788 |
| Three novel sequence variations in the 5' upstream region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene: two polymorphisms and one putative molecular defect. | Bienvenu T | Human genetics | 1995 | PMID: 7540587 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
| http://www.umd.be/CFTR | - | - | - | - |
Text-mined citations for rs181008242 ...
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 Oct 20, 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.