The p.L732* pathogenic mutation (also known as c.2195T>G), located in coding exon 14 of the CFTR gene, results from a T to G substitution at nucleotide position 2195. This changes the amino acid from a leucine to a stop codon within coding exon 14. In one study, this mutation was reported in an individual with congenital bilateral absence of the vas deferens (CBAVD), recurrent bronchitis, and a few gastrointestinal issues in conjunction with a 5T allele (Kanavakis E et al. Mol Hum Reprod, 1998 Apr;4:333-7). In another study, this mutation was seen along with a second CFTR variant in an individual with failure to thrive, chronic cough, chronic sinusitis, and elevated sweat chloride levels (McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8). This variant is assoicated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (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.
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.2195T>G (p.Leu732Ter)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Mar 2017 by
CFTR2
for
Cystic fibrosis
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.2195T>G (p.Leu732Ter)
Variation ID: 53451 Accession: VCV000053451.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117592362 (GRCh38) [ NCBI UCSC ] 7: 117232416 (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 Jan 6, 2018 May 1, 2024 Mar 17, 2017 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.2195T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Leu732Ter nonsense NC_000007.14:g.117592362T>G NC_000007.13:g.117232416T>G NG_016465.4:g.131579T>G LRG_663:g.131579T>G LRG_663t1:c.2195T>G LRG_663p1:p.Leu732Ter - Protein change
- L732*
- Other names
-
p.Leu732*
- Canonical SPDI
- NC_000007.14:117592361: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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. |
|---|---|---|---|---|
| Pathogenic (7) |
reviewed by expert panel
|
Mar 17, 2017 | RCV000056360.16 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 10, 2022 | RCV001269766.6 | |
|
CFTR-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Mar 17, 2017 | RCV001831744.1 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 29, 2023 | RCV003473477.1 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 17, 2017)
|
reviewed by expert panel
Method: research
|
Cystic fibrosis
Affected status: yes
Allele origin:
germline
|
CFTR2
Study: CFTR2
Accession: SCV000071542.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018 |
|
|
|
Pathogenic
(Nov 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: yes
Allele origin:
unknown
|
Mendelics
Accession: SCV000886254.2
First in ClinVar: Jan 06, 2018 Last updated: Dec 11, 2022 |
|
|
|
Pathogenic
(Jan 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004213576.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Jan 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002729463.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L732* pathogenic mutation (also known as c.2195T>G), located in coding exon 14 of the CFTR gene, results from a T to G substitution at … (more)
The p.L732* pathogenic mutation (also known as c.2195T>G), located in coding exon 14 of the CFTR gene, results from a T to G substitution at nucleotide position 2195. This changes the amino acid from a leucine to a stop codon within coding exon 14. In one study, this mutation was reported in an individual with congenital bilateral absence of the vas deferens (CBAVD), recurrent bronchitis, and a few gastrointestinal issues in conjunction with a 5T allele (Kanavakis E et al. Mol Hum Reprod, 1998 Apr;4:333-7). In another study, this mutation was seen along with a second CFTR variant in an individual with failure to thrive, chronic cough, chronic sinusitis, and elevated sweat chloride levels (McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8). This variant is assoicated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (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)
|
|
|
Pathogenic
(Jan 29, 2018)
|
criteria provided, single submitter
Method: curation
|
cystic fibrosis
Affected status: yes
Allele origin:
germline
|
CFTR-France
Accession: SCV001169545.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
|
|
|
Pathogenic
(Mar 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226575.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PP5, PM2, PM3_very_strong, PVS1
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 25, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696889.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Comment:
Variant summary: The CFTR c.2195T>G (p.Leu732X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense … (more)
Variant summary: The CFTR c.2195T>G (p.Leu732X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation of this variant at Leu732 would eliminate part of the CFTR regulator domain, the N terminal transmembrane domain, the AAA+ ATPase domain, and the P-loop NTPase fold domain. Consequently, one in silico tool predicts a damaging outcome for this variant. This variant was found in 1/120718 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). It was reported in many CF patients with at least one patient being homozygous for the variant, indicating pathogenicity. Furthermore, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp1089X, p.Tyr1092X). Additionally, at least one database classified the variant as pathogenic/CF-causing. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450016.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001580681.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu732*) 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.Leu732*) 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). This variant is present in population databases (rs397508350, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with CFTR-related conditions (PMID: 9003508, 23974870). ClinVar contains an entry for this variant (Variation ID: 53451). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jul 28, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132145.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743002.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001974092.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
CFTR-related disorders
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002080720.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
PP4, PP5, PM2, PM3_very_strong, PVS1
Comment:
Variant summary: The CFTR c.2195T>G (p.Leu732X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation of this variant at Leu732 would eliminate part of the CFTR regulator domain, the N terminal transmembrane domain, the AAA+ ATPase domain, and the P-loop NTPase fold domain. Consequently, one in silico tool predicts a damaging outcome for this variant. This variant was found in 1/120718 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). It was reported in many CF patients with at least one patient being homozygous for the variant, indicating pathogenicity. Furthermore, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp1089X, p.Tyr1092X). Additionally, at least one database classified the variant as pathogenic/CF-causing. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Leu732*) 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). This variant is present in population databases (rs397508350, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with CFTR-related conditions (PMID: 9003508, 23974870). ClinVar contains an entry for this variant (Variation ID: 53451). For these reasons, this variant has been classified as 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:
The p.L732* pathogenic mutation (also known as c.2195T>G), located in coding exon 14 of the CFTR gene, results from a T to G substitution at nucleotide position 2195. This changes the amino acid from a leucine to a stop codon within coding exon 14. In one study, this mutation was reported in an individual with congenital bilateral absence of the vas deferens (CBAVD), recurrent bronchitis, and a few gastrointestinal issues in conjunction with a 5T allele (Kanavakis E et al. Mol Hum Reprod, 1998 Apr;4:333-7). In another study, this mutation was seen along with a second CFTR variant in an individual with failure to thrive, chronic cough, chronic sinusitis, and elevated sweat chloride levels (McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8). This variant is assoicated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (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.
Comment:
PP4, PP5, PM2, PM3_very_strong, PVS1
Comment:
Variant summary: The CFTR c.2195T>G (p.Leu732X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation of this variant at Leu732 would eliminate part of the CFTR regulator domain, the N terminal transmembrane domain, the AAA+ ATPase domain, and the P-loop NTPase fold domain. Consequently, one in silico tool predicts a damaging outcome for this variant. This variant was found in 1/120718 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). It was reported in many CF patients with at least one patient being homozygous for the variant, indicating pathogenicity. Furthermore, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp1089X, p.Tyr1092X). Additionally, at least one database classified the variant as pathogenic/CF-causing. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Leu732*) 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). This variant is present in population databases (rs397508350, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with CFTR-related conditions (PMID: 9003508, 23974870). ClinVar contains an entry for this variant (Variation ID: 53451). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. | Lakeman P | Genetic testing | 2008 | PMID: 18373402 |
| Negative genetic neonatal screening for cystic fibrosis caused by compound heterozygosity for two large CFTR rearrangements. | Girardet A | Clinical genetics | 2007 | PMID: 17850636 |
| Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. | McGinniss MJ | Human genetics | 2005 | PMID: 16189704 |
| Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. | Claustres M | Human mutation | 2000 | PMID: 10923036 |
| Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. | Cohn JA | The New England journal of medicine | 1998 | PMID: 9725922 |
| Cystic fibrosis mutation screening in CBAVD patients and men with obstructive azoospermia or severe oligozoospermia. | Kanavakis E | Molecular human reproduction | 1998 | PMID: 9620832 |
| Characterization of more than 85% of cystic fibrosis alleles in the Greek population, including five novel mutations. | Tzetis M | Human genetics | 1997 | PMID: 9003508 |
| Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR. | Yang Y | Human molecular genetics | 1993 | PMID: 7691345 |
| 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 |
| https://cftr2.org | - | - | - | - |
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Text-mined citations for rs397508350 ...
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.