ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3068T>G (p.Ile1023Arg)
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.
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(1); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3068T>G (p.Ile1023Arg)
Variation ID: 495923 Accession: VCV000495923.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117610598 (GRCh38) [ NCBI UCSC ] 7: 117250652 (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 Mar 17, 2018 Feb 20, 2024 Oct 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3068T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ile1023Arg missense NC_000007.14:g.117610598T>G NC_000007.13:g.117250652T>G NG_016465.4:g.149815T>G NG_056128.2:g.3652T>G LRG_663:g.149815T>G LRG_663t1:c.3068T>G LRG_663p1:p.Ile1023Arg - Protein change
- I1023R
- Other names
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- Canonical SPDI
- NC_000007.14:117610597:T:G
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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 |
3598 | 4891 | |
LOC111674472 | - | - | - | GRCh38 | - | 376 |
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
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Jan 4, 2016 | RCV000590216.1 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2022 | RCV001226278.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 5, 2023 | RCV003471940.1 |
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
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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
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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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Uncertain significance
(Jan 04, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696945.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Isoleucine (I) with a large size and … (more)
Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Isoleucine (I) with a large size and basic Arginine (R). 4/5 in silico tools predict the variant to be disease causing. It was observed in the East Asian subcohort of the ExAC project at an allele frequency of 0.011% which does not exceed the maximal expected allele frequency of a disease causing CFTR allele: 1.2%. The variant was reported in heterozygosity with c.1898+5G > T in two Taiwanese brothers with recurrent pneumonia and bronchiolitis. One of the brothers had sweat chloride levels >100 meq/l indicating a diagnosis of CF (Chen_JFMA_2012; Liu_JMII_2014). Additionally, a poster presented at the 2014 American Society of Human Genetics reported three unrelated Chinese CF patients who carried the variant (Chung_2014). Furthermore, CFTR and UMD databases list several mutations affecting the same nucleotide as the variant of interest c.3063_3068delAGTGAT p.Ile1023_Val1024del6; c.3068_3072delTAGTG p.Ile1023SerfsX22; c.3068T>C p.Ile1023Thr and c.3067_3072del p.Ile1023_Val1024del indicating the variant to be a mutational hotspot. Considering all available lines of evidence, the variant of interest is classified as VUS-possibly pathogenic, until more information becomes available. (less)
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Likely pathogenic
(May 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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NxGen MDx
Accession: SCV001573125.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
This missense variant (c.3068T>G) in a hotspot on exon 19 of CFTR (PM1) and gnomAD databases indicate low allele frequency (PM2). Computational models produce mostly … (more)
This missense variant (c.3068T>G) in a hotspot on exon 19 of CFTR (PM1) and gnomAD databases indicate low allele frequency (PM2). Computational models produce mostly pathogenic verdicts for this variant (PP3). This variant has been reported in heterozygosity with c.1898+5G>T in two Taiwanese brothers with recurrent pneumonia and bronchiolitis. One of the brothers had sweat chloride levels >100 meq/l indicating a diagnosis of cystic fibrosis (Chen el al. PMID 23089694; Liu et al. PMID 22992393). There are 4 additional cases in Leung et al. PMID 28116329 where the authors suggest this variant may be a founder mutation in southern Han Chinese. Leung et al. also conducted functional analysis demonstrating that p.Ile1023Arg leads to a trafficking defect during CFTR maturation without affecting the gating function. We interpret c.3068T>G to be likely pathogenic. (less)
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Likely pathogenic
(Aug 07, 2019)
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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: SCV002753007.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.I1023R variant (also known as c.3068T>G), located in coding exon 19 of the CFTR gene, results from a T to G substitution at nucleotide … (more)
The p.I1023R variant (also known as c.3068T>G), located in coding exon 19 of the CFTR gene, results from a T to G substitution at nucleotide position 3068. The isoleucine at codon 1023 is replaced by arginine, an amino acid with similar properties. This variant has been identified in several individuals with symptoms of cystic fibrosis with a second CFTR variant and has been suggested to be a Southern Chinese founder mutation (Chen CH et al. J. Formos. Med. Assoc., 2012 Oct;111:580-3; Liu LC et al. J Microbiol Immunol Infect, 2014 Aug;47:358-61; Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). One homozygous individual presented at 4 months of age with elevated sweat chloride levels, respiratory symptoms, and pancreatic insufficiency (Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). In HeLa cells, this variant demonstrated reduced levels of mature CFTR protein compared to wild type (Leung GK et al. Mol Genet Genomic Med, 2017 Jan;5:40-49). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Oct 05, 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: SCV004213332.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 15, 2022)
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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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Invitae
Accession: SCV001398586.6
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact … (more)
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 28116329). ClinVar contains an entry for this variant (Variation ID: 495923). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 22992393, 23089694, 28116329). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs756219310, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1023 of the CFTR protein (p.Ile1023Arg). (less)
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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 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 |
CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis. | Leung GK | Molecular genetics & genomic medicine | 2016 | PMID: 28116329 |
Cystic fibrosis: experience in one institution. | Liu LC | Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi | 2014 | PMID: 22992393 |
Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis. | Chen CH | Journal of the Formosan Medical Association = Taiwan yi zhi | 2012 | PMID: 23089694 |
Text-mined citations for rs756219310 ...
HelpRecord last updated Feb 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.