ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3983T>C (p.Ile1328Thr)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3983T>C (p.Ile1328Thr)
Variation ID: 439080 Accession: VCV000439080.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117664707 (GRCh38) [ NCBI UCSC ] 7: 117304761 (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 Sep 30, 2017 May 1, 2024 Jul 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3983T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ile1328Thr missense NC_000007.14:g.117664707T>C NC_000007.13:g.117304761T>C NG_016465.4:g.203924T>C LRG_663:g.203924T>C LRG_663t1:c.3983T>C LRG_663p1:p.Ile1328Thr - Protein change
- I1328T
- Other names
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- Canonical SPDI
- NC_000007.14:117664706:T:C
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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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 | ||
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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
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. |
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CFTR | - | - |
GRCh38 GRCh37 |
3821 | 5195 |
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. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 6, 2019 | RCV000507454.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 27, 2023 | RCV000723504.5 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Oct 2, 2022 | RCV000804416.8 | |
CFTR-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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May 28, 2018 | RCV001829442.1 |
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. |
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Uncertain significance
(Feb 17, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000700500.2
First in ClinVar: Sep 30, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Uncertain significance
(Mar 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360547.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: CFTR c.3983T>C (p.Ile1328Thr) results in a non-conservative amino acid change located in the ATPase domain (IPR003593) of the encoded protein sequence. Five of … (more)
Variant summary: CFTR c.3983T>C (p.Ile1328Thr) results in a non-conservative amino acid change located in the ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 276854 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3983T>C has been reported in the literature found during newborn screening in an infant who also carried a known pathogenic variant (F508del) and was found to have normal sweat chloride levels (<30mmol/L) (Ooi 2015). Furthermore, Tamura et al. 2018 reported the variant in one patient with pancreatic cancer, but authors concluded that occurrence of variants in the CFTR gene did not correlate with incidence of pancreatic cancer in their study. These reports do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk. A co-occurrence with a pathogenic variant has been reported in our internal database (SPINK1 c.101A>G (p.Asn34Ser)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002027529.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Uncertain significance
(Aug 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601113.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022 |
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Uncertain significance
(Oct 02, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000944327.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1328 of the CFTR protein (p.Ile1328Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1328 of the CFTR protein (p.Ile1328Thr). This variant is present in population databases (rs115762793, gnomAD 0.006%). This missense change has been observed in individual(s) with an inconclusive diagnosis of cystic fibrosis (CF) via newborn screening (PMID: 25963003). ClinVar contains an entry for this variant (Variation ID: 439080). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jul 27, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004565314.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.3983T>C; p.Ile1328Thr variant (rs115762793) is reported in the literature in an individual with a single-organ manifestation suggestive of CF (Ooi 2012), and in … (more)
The CFTR c.3983T>C; p.Ile1328Thr variant (rs115762793) is reported in the literature in an individual with a single-organ manifestation suggestive of CF (Ooi 2012), and in an infant with a positive newborn screen who was also heterozygous for F508del but had normal sweat chloride levels (Ooi 2015). The p.Ile1328Thr variant is also reported in the CFTR France database in an individual with congenital bilateral absence of the vas deferens (CBAVD; see link), and is reported in ClinVar (Variation ID: 439080). This variant is only found on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.943). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: CFTR France database link: https://cftr.iurc.montp.inserm.fr/cgi-bin/affiche.cgi?variant=c.3983T%3EC&provenance=0 Ooi CY et al. Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? Thorax. 2012 Jul;67(7):618-24. PMID: 22504961. Ooi CY et al. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics. 2015 Jun;135(6):e1377-85. PMID: 25963003. (less)
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Uncertain significance
(May 21, 2021)
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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: SCV002623165.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.I1328T variant (also known as c.3983T>C), located in coding exon 25 of the CFTR gene, results from a T to C substitution at nucleotide … (more)
The p.I1328T variant (also known as c.3983T>C), located in coding exon 25 of the CFTR gene, results from a T to C substitution at nucleotide position 3983. The isoleucine at codon 1328 is replaced by threonine, an amino acid with similar properties. This variant was detected in an individual who had single-organ manifestation suggestive of cystic fibrosis; the individual also had p.R347P in the CFTR gene (Ooi CY et al. Thorax, 2012 Jul;67:618-24). This alteration was also described in an infant with a positive newborn screen based on elevated immunoreactive trypsinogen (IRT), subsequent normal sweat chloride levels, who was heterozygous for p.F508del (Ooi CY et al. Pediatrics, 2015 Jun;135:e1377-85). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(May 28, 2018)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002075916.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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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Inconclusive diagnosis of cystic fibrosis after newborn screening. | Ooi CY | Pediatrics | 2015 | PMID: 25963003 |
Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? | Ooi CY | Thorax | 2012 | PMID: 22504961 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
Text-mined citations for rs115762793 ...
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.