ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1453A>T (p.Ser485Cys)
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.1453A>T (p.Ser485Cys)
Variation ID: 53258 Accession: VCV000053258.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117559524 (GRCh38) [ NCBI UCSC ] 7: 117199578 (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 Aug 5, 2018 May 1, 2024 Jun 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1453A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ser485Cys missense NC_000007.14:g.117559524A>T NC_000007.13:g.117199578A>T NG_016465.4:g.98741A>T LRG_663:g.98741A>T LRG_663t1:c.1453A>T LRG_663p1:p.Ser485Cys - Protein change
- S485C
- Other names
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- Canonical SPDI
- NC_000007.14:117559523:A:T
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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 (T)
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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) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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
Help
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 |
3704 | 5025 | |
CFTR-AS1 | - | - | - | GRCh38 | - | 490 |
Conditions - Germline
Condition
Help
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 (3) |
criteria provided, multiple submitters, no conflicts
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Nov 14, 2022 | RCV000666426.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 16, 2023 | RCV003317059.1 |
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
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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
(Apr 05, 2017)
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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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Counsyl
Accession: SCV000790716.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Sep 10, 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: SCV002160362.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 485 of the CFTR protein … (more)
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 485 of the CFTR protein (p.Ser485Cys). This variant is present in population databases (rs138427145, gnomAD 0.08%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 22483971, 32777524). ClinVar contains an entry for this variant (Variation ID: 53258). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. 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
(Jun 16, 2023)
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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: SCV004020685.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CFTR c.1453A>T (p.Ser485Cys) results in a non-conservative amino acid change located in the ATP-binding domain (IPR003439) of the encoded protein sequence. Five of … (more)
Variant summary: CFTR c.1453A>T (p.Ser485Cys) results in a non-conservative amino acid change located in the ATP-binding domain (IPR003439) 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 5.6e-05 in 251344 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (5.6e-05 vs 0.013), allowing no conclusion about variant significance. c.1453A>T has been reported in the literature in affected individuals of East Asian ethnicity, predominantly in individuals affected with CBAVD (e.g., Li_2012, Lu_2013, Lu_2014, Luo_2021), but also in individuals with bronchiectasis (e.g., Schrijver_2008; SickKids database) and nontuberculous mycobacteria lung disease (e.g., Jang_2013). However, there was not strong evidence for causality in any of these cases (e.g., lack of co-segregation and co-occurence data as well as uninformative genotypes). These reports therefore do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23514810, 22483971, 24559724, 23953609, 32777524, 35313924, 18556774). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 , and all laboratories classified 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
(Nov 14, 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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Ambry Genetics
Accession: SCV002701883.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S485C variant (also known as c.1453A>T), located in coding exon 11 of the CFTR gene, results from an A to T substitution at nucleotide … (more)
The p.S485C variant (also known as c.1453A>T), located in coding exon 11 of the CFTR gene, results from an A to T substitution at nucleotide position 1453. The serine at codon 485 is replaced by cysteine, an amino acid with dissimilar properties. This variant was identified in two individuals with congenital absence of the vas deferens; in one individual it was detected in conjunction with the 5T allele, but the phase was not provided (Li H et al. J. Cyst. Fibros. 2012 Jul; 11(4):316-23; Lu S et al. Urology, 2013 Oct; 82(4):824-8). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear. (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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Systematic estimation of cystic fibrosis prevalence in Chinese and genetic spectrum comparison to Caucasians. | Ni Q | Orphanet journal of rare diseases | 2022 | PMID: 35313924 |
Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. | Luo S | Gene | 2021 | PMID: 32777524 |
Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling. | de Souza DAS | Andrology | 2018 | PMID: 29216686 |
Association of cystic fibrosis transmembrane-conductance regulator gene mutation with negative outcome of intracytoplasmic sperm injection pregnancy in cases of congenital bilateral absence of vas deferens. | Lu S | Fertility and sterility | 2014 | PMID: 24559724 |
Different cystic fibrosis transmembrane conductance regulator mutations in Chinese men with congenital bilateral absence of vas deferens and other acquired obstructive azoospermia. | Lu S | Urology | 2013 | PMID: 23953609 |
Association of CFTR gene variants with nontuberculous mycobacterial lung disease in a Korean population with a low prevalence of cystic fibrosis. | Jang MA | Journal of human genetics | 2013 | PMID: 23514810 |
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. | Li H | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2012 | PMID: 22483971 |
Multiplex ligation-dependent probe amplification identification of whole exon and single nucleotide deletions in the CFTR gene of Hispanic individuals with cystic fibrosis. | Schrijver I | The Journal of molecular diagnostics : JMD | 2008 | PMID: 18556774 |
Text-mined citations for rs138427145 ...
HelpRecord last updated May 01, 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.