In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1284534, 23974870, 9305991, 12394343, 10653141, 11484207, 22658665, 22975760, 20021716, 15287992, 26990548, 7517268, 15017334, 18456578, 18685558, 16822950, 11242048, 19491324, 15371902)
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.443T>C (p.Ile148Thr)
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.
(17)
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(2); Benign(9); Likely benign(5)
Uncertain significance(2); Benign(9); Likely benign(5)
17
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.443T>C (p.Ile148Thr)
Variation ID: 38850 Accession: VCV000038850.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117531068 (GRCh38) [ NCBI UCSC ] 7: 117171122 (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 Oct 2, 2016 Oct 20, 2024 Apr 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.443T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ile148Thr missense NC_000007.14:g.117531068T>C NC_000007.13:g.117171122T>C NG_016465.4:g.70285T>C LRG_663:g.70285T>C LRG_663t1:c.443T>C LRG_663p1:p.Ile148Thr P13569:p.Ile148Thr - Protein change
- I148T
- Other names
-
NM_000492.3(CFTR):c.443T>C(p.Ile148Thr)
- Canonical SPDI
- NC_000007.14:117531067:T:C
-
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.
-
0.00140 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
The Genome Aggregation Database (gnomAD) 0.00083
Trans-Omics for Precision Medicine (TOPMed) 0.00101
1000 Genomes Project 30x 0.00109
1000 Genomes Project 0.00140
The Genome Aggregation Database (gnomAD), exomes 0.00178
Exome Aggregation Consortium (ExAC) 0.00187
- 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 |
3825 | 5200 | |
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 (10) |
criteria provided, conflicting classifications
|
Apr 30, 2024 | RCV000047138.36 | |
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 24, 2019 | RCV000079009.26 | |
|
CFTR-related disorder
|
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV001095251.13 |
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 15, 2023 | RCV001705619.25 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000304500.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
|
Likely benign
(Apr 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790922.1
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
|
|
|
Likely benign
(Feb 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001830562.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1284534, 23974870, 9305991, 12394343, 10653141, 11484207, 22658665, 22975760, 20021716, 15287992, 26990548, 7517268, 15017334, 18456578, 18685558, 16822950, 11242048, 19491324, 15371902) (less)
|
|
|
Benign
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000075151.11
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
|
|
|
Likely benign
(Jun 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001737321.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Sex: mixed
|
|
|
Benign
(Dec 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469505.2
First in ClinVar: Jan 26, 2021 Last updated: Dec 31, 2022 |
|
|
|
Benign
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV000886144.3
First in ClinVar: Aug 04, 2018 Last updated: Aug 25, 2023 |
|
|
|
Benign
(Aug 06, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110878.8
First in ClinVar: Jan 17, 2014 Last updated: Oct 02, 2016 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Benign
(Jun 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425332.1
First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020 |
|
|
|
Uncertain significance
(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: SCV002574072.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Comment:
This variant was identified in 2 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 2 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: PM5, PP4, BS2, BS3, BP2 (less)
Number of individuals with the variant: 2
|
|
|
Benign
(Nov 15, 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: SCV000603005.5
First in ClinVar: Oct 02, 2016 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Mar 13, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001184227.4
First in ClinVar: Mar 16, 2020 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)
|
|
|
Likely benign
(Apr 30, 2024)
|
criteria provided, single submitter
Method: curation
|
Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803630.2
First in ClinVar: Aug 04, 2018 Last updated: May 07, 2024 |
Comment:
This variant is interpreted as a likely benign, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in … (more)
This variant is interpreted as a likely benign, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:12394343). (less)
|
|
|
Likely benign
(Oct 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004158944.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
CFTR: PM5, BS2
Number of individuals with the variant: 3
|
|
|
Benign
(Jan 29, 2018)
|
criteria provided, single submitter
Method: curation
|
cystic fibrosis
Affected status: yes, no
Allele origin:
germline
|
CFTR-France
Accession: SCV001169190.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
the variant does not result in CFTR-RD neither
Observation 1: Observation 2: |
|
|
Uncertain significance
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
CFTR-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000466503.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
|
|
|
Benign
(Aug 06, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453949.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant was identified in 2 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: PM5, PP4, BS2, BS3, BP2
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:
This variant is interpreted as a likely benign, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:12394343).
Comment:
CFTR: PM5, BS2
Comment:
the variant does not result in CFTR-RD neither
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
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:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1284534, 23974870, 9305991, 12394343, 10653141, 11484207, 22658665, 22975760, 20021716, 15287992, 26990548, 7517268, 15017334, 18456578, 18685558, 16822950, 11242048, 19491324, 15371902)
Comment:
This variant was identified in 2 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: PM5, PP4, BS2, BS3, BP2
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:
This variant is interpreted as a likely benign, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:12394343).
Comment:
CFTR: PM5, BS2
Comment:
the variant does not result in CFTR-RD neither
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
| Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis. | Dal'Maso VB | Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia | 2013 | PMID: 23670503 |
| Mutation-specific potency and efficacy of cystic fibrosis transmembrane conductance regulator chloride channel potentiators. | Caputo A | The Journal of pharmacology and experimental therapeutics | 2009 | PMID: 19491324 |
| Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. | Castellani C | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2008 | PMID: 18456578 |
| Abnormal regulatory interactions of I148T-CFTR and the epithelial Na+ channel in Xenopus oocytes. | Suaud L | American journal of physiology. Cell physiology | 2007 | PMID: 16822950 |
| Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. | Watson MS | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15371902 |
| Are p.I148T, p.R74W and p.D1270N cystic fibrosis causing mutations? | Claustres M | BMC medical genetics | 2004 | PMID: 15287992 |
| Frequency of the cystic fibrosis 3199del6 mutation in individuals heterozygous for I148T. | Buller A | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15017334 |
| The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis. | Rohlfs EM | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12394343 |
| Cystic fibrosis screening using the College panel: platform comparison and lessons learned from the first 20,000 samples. | Strom CM | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12172395 |
| Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. | Choi JY | Nature | 2001 | PMID: 11242048 |
| Disease-associated mutations in cytoplasmic loops 1 and 2 of cystic fibrosis transmembrane conductance regulator impede processing or opening of the channel. | Seibert FS | Biochemistry | 1997 | PMID: 9305991 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs35516286 ...
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 27, 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.