Variant summary: CFTR c.50dupT (p.Ser18GlnfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations upstream and downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 4e-06 in 250742 control chromosomes (gnomAD). the variant c.50dupT (also described in the literature as c.43_44insT and 175insT) has been reported in multiple homozygous and compound heterozygous individuals affected with Cystic Fibrosis and related phenotypes (Schaedel_1995, Schaedel_1999, Prontera_2016, Ge_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.50dup (p.Ser18fs)
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.
(9)
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.
Pathogenic
9
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.50dup (p.Ser18fs)
Variation ID: 53944 Accession: VCV000053944.13
- Type and length
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Duplication, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117480137-117480138 (GRCh38) [ NCBI UCSC ] 7: 117120191-117120192 (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 25, 2018 Aug 25, 2024 Feb 6, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.50dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ser18fs frameshift NM_000492.4:c.50dupT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000492.3:c.43_44insT NC_000007.14:g.117480144dup NC_000007.13:g.117120198dup NG_016465.4:g.19361dup NG_056120.2:g.4174dup LRG_663:g.19361dup LRG_663t1:c.50dup - Protein change
- S18fs
- Other names
-
175insT
- Canonical SPDI
- NC_000007.14:117480137:TTTTTTT:TTTTTTTT
-
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.
- -
- 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 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 19, 2023 | RCV000577158.15 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 17, 2017 | RCV001826686.9 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV003137586.12 |
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
(Dec 10, 2021)
|
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: SCV001337845.2
First in ClinVar: Jun 18, 2020 Last updated: Jan 08, 2022 |
Comment:
Variant summary: CFTR c.50dupT (p.Ser18GlnfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CFTR c.50dupT (p.Ser18GlnfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations upstream and downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 4e-06 in 250742 control chromosomes (gnomAD). the variant c.50dupT (also described in the literature as c.43_44insT and 175insT) has been reported in multiple homozygous and compound heterozygous individuals affected with Cystic Fibrosis and related phenotypes (Schaedel_1995, Schaedel_1999, Prontera_2016, Ge_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003820706.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243328.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Pathogenic
(Oct 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004295529.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser18Glnfs*27) 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.Ser18Glnfs*27) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with congenital absence of the vas deferens (PMID: 31709488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53944). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197447.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Dec 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001469036.1
First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
Comment:
This frameshift variant results in a premature stop codon, likely leading to nonsense-mediated decay and lack of protein production. CFTR c.50dupT has been reported in … (more)
This frameshift variant results in a premature stop codon, likely leading to nonsense-mediated decay and lack of protein production. CFTR c.50dupT has been reported in the homozygous state in individuals with a clinical diagnosis of cystic fibrosis. This variant (rs397508714*) is rare (<0.1%) in a large population dataset (gnomAD: 1/250742 total alleles; 0.0004%; homozygotes) and has been reported in ClinVar. We consider this variant to be pathogenic. (less)
|
|
|
Pathogenic
(Sep 05, 2022)
|
criteria provided, single submitter
Method: curation
|
Cystic fibrosis
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002573958.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Comment:
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project … (more)
This variant was identified in 1 patient 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: PVS1, PM3_STR, PM2_SUP, PP4 (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
CFTR-related disorders
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002080060.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
CFTR-related disorders
Affected status: yes
Allele origin:
germline
|
ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000679139.1
First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Ser18Glnfs*27) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with congenital absence of the vas deferens (PMID: 31709488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53944). For these reasons, this variant has been classified as Pathogenic.
Comment:
This frameshift variant results in a premature stop codon, likely leading to nonsense-mediated decay and lack of protein production. CFTR c.50dupT has been reported in the homozygous state in individuals with a clinical diagnosis of cystic fibrosis. This variant (rs397508714*) is rare (<0.1%) in a large population dataset (gnomAD: 1/250742 total alleles; 0.0004%; homozygotes) and has been reported in ClinVar. We consider this variant to be pathogenic.
Comment:
This variant was identified in 1 patient 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: PVS1, PM3_STR, PM2_SUP, PP4
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:
Variant summary: CFTR c.50dupT (p.Ser18GlnfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations upstream and downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 4e-06 in 250742 control chromosomes (gnomAD). the variant c.50dupT (also described in the literature as c.43_44insT and 175insT) has been reported in multiple homozygous and compound heterozygous individuals affected with Cystic Fibrosis and related phenotypes (Schaedel_1995, Schaedel_1999, Prontera_2016, Ge_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Ser18Glnfs*27) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with congenital absence of the vas deferens (PMID: 31709488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53944). For these reasons, this variant has been classified as Pathogenic.
Comment:
This frameshift variant results in a premature stop codon, likely leading to nonsense-mediated decay and lack of protein production. CFTR c.50dupT has been reported in the homozygous state in individuals with a clinical diagnosis of cystic fibrosis. This variant (rs397508714*) is rare (<0.1%) in a large population dataset (gnomAD: 1/250742 total alleles; 0.0004%; homozygotes) and has been reported in ClinVar. We consider this variant to be pathogenic.
Comment:
This variant was identified in 1 patient 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: PVS1, PM3_STR, PM2_SUP, PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A rare frameshift variant in trans with the IVS9-5T allele of CFTR in a Chinese pedigree with congenital aplasia of vas deferens. | Ge B | Journal of assisted reproduction and genetics | 2019 | PMID: 31709488 |
| A Clinical and Molecular Survey of 62 Cystic Fibrosis Patients from Umbria (Central Italy) Disclosing a High Frequency (2.4%) of the 2184insA Allele: Implications for Screening. | Prontera P | Public health genomics | 2016 | PMID: 27728908 |
| Recommendations for quality improvement in genetic testing for cystic fibrosis. European Concerted Action on Cystic Fibrosis. | Dequeker E | European journal of human genetics : EJHG | 2000 | PMID: 11108532 |
| Three common CFTR mutations should be included in a neonatal screening programme for cystic fibrosis in Sweden. | Schaedel C | Clinical genetics | 1999 | PMID: 10636451 |
| Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. | Cohn JA | The New England journal of medicine | 1998 | PMID: 9725922 |
| Cystic fibrosis caused by homozygosity for the CFTR gene mutation 175insT. | Schaedel C | Acta paediatrica (Oslo, Norway : 1992) | 1995 | PMID: 8563237 |
| 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 |
Text-mined citations for rs397508714 ...
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 Nov 25, 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.