ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.413_415dup (p.Leu138dup)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.413_415dup (p.Leu138dup)
Variation ID: 53905 Accession: VCV000053905.20
- Type and length
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Duplication, 3 bp
- Location
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Cytogenetic: 7q31.2 7: 117531036-117531037 (GRCh38) [ NCBI UCSC ] 7: 117171090-117171091 (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 Aug 11, 2024 Aug 31, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.413_415dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Leu138dup inframe insertion NM_000492.4:c.413_415dupTAC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000492.3:c.413_415dupTAC NC_000007.14:g.117531038_117531040dup NC_000007.13:g.117171092_117171094dup NG_016465.4:g.70255_70257dup LRG_663:g.70255_70257dup - Protein change
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- Other names
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546insCTA oder L138ins
- Canonical SPDI
- NC_000007.14:117531036:CTAC:CTACTAC
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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.
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- Links
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 |
3826 | 5201 |
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
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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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Pathogenic (8) |
reviewed by expert panel
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Aug 31, 2018 | RCV000577362.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 25, 2021 | RCV001509310.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 28, 2023 | RCV004566881.1 |
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
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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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Pathogenic
(Aug 31, 2018)
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reviewed by expert panel
Method: research
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR2
Accession: SCV000924246.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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Pathogenic
(Dec 28, 2023)
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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: SCV005057460.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Feb 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715936.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4_Moderate, PM2, PM3, PM4, PP5
Number of individuals with the variant: 1
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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: SCV002574101.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Comment:
This variant was identified in 4 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a … (more)
This variant was identified in 4 unrelated patients 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_SUP, PM2_SUP, PM3_STR, PM4_SUP, PP4 (less)
Number of individuals with the variant: 4
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Pathogenic
(Oct 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust
Accession: SCV004814226.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
Criteria Codes: PM2 PM3_VStr PM4
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Pathogenic
(Oct 12, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001583173.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant, c.413_415dup, results in the insertion of 1 amino acid(s) of the CFTR protein (p.Leu138dup), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.413_415dup, results in the insertion of 1 amino acid(s) of the CFTR protein (p.Leu138dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752803445, gnomAD 0.004%). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 9272157, 16189704, 28546993, 30548586). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 546insCTA and c.411_412insCTA. ClinVar contains an entry for this variant (Variation ID: 53905). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CFTR function (PMID: 30046002). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 21, 2024)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338283.2
First in ClinVar: Jun 22, 2020 Last updated: Apr 15, 2024 |
Comment:
Variant summary: CFTR c.413_415dupTAC (p.Leu138dup) results in an in-frame duplication that is predicted to duplicate 1 amino acids into the encoded protein. The variant allele … (more)
Variant summary: CFTR c.413_415dupTAC (p.Leu138dup) results in an in-frame duplication that is predicted to duplicate 1 amino acids into the encoded protein. The variant allele was found at a frequency of 4e-06 in 250744 control chromosomes. c.413_415dupTAC has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Behar_2017, Guo_2018, McGinniss_2005, Petrova_2019, Walkowiak_2001). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant confers residual function 1.6% of wild-type (Han_2018). The following publications have been ascertained in the context of this evaluation (PMID: 9272157, 11589722, 16189704, 28546993, 30046002, 30548586, 30558651).ClinVar contains an entry for this variant (Variation ID: 53905). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 08, 2024)
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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: SCV002628550.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The c.413_415dupTAC pathogenic mutation (also known as p.L138dup), located in coding exon 4 of the CFTR gene, results from an in-frame duplication of TAC at … (more)
The c.413_415dupTAC pathogenic mutation (also known as p.L138dup), located in coding exon 4 of the CFTR gene, results from an in-frame duplication of TAC at nucleotide positions 413 to 415. This results in the duplication of an extra residue between codons 138 and 139. In our laboratory, this variant has been detected in trans with a pathogenic mutation in CFTR in an individual with intermediate sweat chloride levels (Ambry internal data). In an analysis of 40 CFTR mutations in Russian cystic fibrosis (CF) patients, this variant (reported as L138ins) was detected in 1.8% of the chromosomes (Adyan TA et al. Russ J Genet, 2018 Oct;54:1235-1244). This mutation was reported in a Polish male with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with a 5T allele (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). This alteration was also described in an individual with CF in conjunction with the c.3717+12191C>T mutation; however, the phase is unclear (Behar DM et al. Mol Genet Genomic Med, 2017 May;5:223-236). Based on internal structural analysis, this pathogenic variant is anticipated to result in a significant decrease in structural stability (Liu F et al. Cell, 2017 Mar;169:85-95.e8). In addition, human CF bronchial epithelial (CFBE) cells stably expressing this mutation (reported as L138ins) had only 1.6% of CFTR function, compared to cells expressing wild-type CFTR protein (Han ST et al. JCI Insight, 2018 Jul;3:). Furthermore, the duplication has an overall frequency of approximately 0.0004% (1/250744) in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(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: SCV001454015.1
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: SCV000679461.1
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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Clinical Presentation of the c.3844T>C (p.Trp1282Arg, W1282R) Variant in Russian Cystic Fibrosis Patients. | Petrova NV | Genes | 2020 | PMID: 32992607 |
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients. | Petrova NV | Genes | 2020 | PMID: 32429104 |
Comprehensive genotyping reveals novel CFTR variants in cystic fibrosis patients from the Russian Federation. | Petrova NV | Clinical genetics | 2019 | PMID: 30548586 |
Clinical and genetic characteristics of cystic fibrosis in CHINESE patients: a systemic review of reported cases. | Guo X | Orphanet journal of rare diseases | 2018 | PMID: 30558651 |
Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators. | Han ST | JCI insight | 2018 | PMID: 30046002 |
Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. | Behar DM | Molecular genetics & genomic medicine | 2017 | PMID: 28546993 |
Molecular Structure of the Human CFTR Ion Channel. | Liu F | Cell | 2017 | PMID: 28340353 |
Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? | Dorfman R | Clinical genetics | 2010 | PMID: 20059485 |
Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. | McGinniss MJ | Human genetics | 2005 | PMID: 16189704 |
Analysis of exocrine pancreatic function in cystic fibrosis: one mild CFTR mutation does not exclude pancreatic insufficiency. | Walkowiak J | European journal of clinical investigation | 2001 | PMID: 11589722 |
Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. | Dörk T | Human genetics | 1997 | PMID: 9272157 |
https://cftr2.org | - | - | - | - |
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Text-mined citations for rs397508686 ...
HelpRecord 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.