ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1731C>T (p.Tyr577=)
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.
Uncertain significance(8); Likely benign(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.1731C>T (p.Tyr577=)
Variation ID: 35832 Accession: VCV000035832.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117590404 (GRCh38) [ NCBI UCSC ] 7: 117230458 (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 Feb 6, 2014 May 1, 2024 Feb 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1731C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Tyr577= synonymous NC_000007.14:g.117590404C>T NC_000007.13:g.117230458C>T NG_016465.4:g.129621C>T LRG_663:g.129621C>T LRG_663t1:c.1731C>T LRG_663p1:p.Tyr577= - Protein change
- Other names
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- Canonical SPDI
- NC_000007.14:117590403:C: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00021
Exome Aggregation Consortium (ExAC) 0.00023
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 |
3712 | 5035 |
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
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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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 11, 2024 | RCV000029487.24 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2024 | RCV001508586.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 5, 2022 | RCV003466875.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 29, 2023 | RCV001420715.10 |
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
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
(Dec 03, 2020)
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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: SCV001477819.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 08, 2022 |
Comment:
The CFTR c.1731C>T; p.Tyr577Tyr variant (rs55928397), is reported in the literature in an individual affected with cystic fibrosis (SickKids CFTR database). This variant is found … (more)
The CFTR c.1731C>T; p.Tyr577Tyr variant (rs55928397), is reported in the literature in an individual affected with cystic fibrosis (SickKids CFTR database). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (46/128572 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 35832). This is a synonymous variant in a weakly conserved nucleotide; however, it occurs in an exonic splicing enhancer element and minigene assays indicate it may lead to increased skipping of exon 12 (Amaral 2004, Fernandez Alanis 2012, Pagani 2005), although this has not been demonstrated in patient cells with this variant. Given the lack of clinical and functional data, the significance of the c.1731C>T variant is uncertain at this time. References: SickKids CFTR database entry for p.Tyr577Tyr: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=755 Amaral MD et al. Quantitative methods for the analysis of CFTR transcripts/splicing variants. J Cyst Fibros. 2004 Aug;3 Suppl 2:17-23. Fernandez Alanis et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum Mol Genet. 2012 Jun 1;21(11):2389-98. Pagani F et al. Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. Proc Natl Acad Sci U S A. 2005 May 3;102(18):6368-72. (less)
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Uncertain significance
(Dec 05, 2022)
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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: SCV004215759.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Oct 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221666.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00036 (46/128572 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.00036 (46/128572 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with idiopathic chronic pancreatitis (PMIDs: 18687795 (2008) and 25492507 (2015)). Functional studies predict exon 12 skipping and did not show any detectable protein (PMIDs: 15463919 (2004), 22362925 (2012), 22591852 (2012), and 32935393 (2020)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CFTR mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Feb 18, 2021)
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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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Revvity Omics, Revvity
Accession: SCV003831646.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely benign
(Jan 11, 2024)
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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: SCV001620988.4
First in ClinVar: May 16, 2021 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jul 22, 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: SCV001822083.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Aug 29, 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: SCV000052138.5
First in ClinVar: Apr 04, 2013 Last updated: Oct 04, 2023 |
Comment:
Variant summary: CFTR c.1731C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. Multiple functional … (more)
Variant summary: CFTR c.1731C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. Multiple functional studies showed that this variant has an effect on splicing, with as little as approximately 5% exon 13 inclusion (legacy name exon 12), however this effect is dependent on other neighboring variants (e.g. Raponi_2006, Pagani_2003, Amaral_2004, Fernandez Alanis_2012, Donega_2020). At-least one recent functional study reports no significant effect of this variant on splicing (Ramalho_2015). To our knowledge no studies reporting a functional impact of this variant on CFTR channel activity have been reported. The variant allele was found at a frequency of 0.00021 in 250348 control chromosomes (gnomAD and Audrezet_2008). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00021 vs 0.013), allowing no conclusion about variant significance. c.1731C>T has been reported in the literature in individuals affected with idiopathic chronic pancreatitis (e.g. Audrezet_2008, Nakano_2015). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The following publications have been ascertained in the context of this evaluation (PMID: 15463919, 18687795, 32935393, 23890012, 22362925, 25492507, 15840711, 25735457, 17172597, 22591852, 26761715). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments ranging from Likely pathogenic (n=1); Likely benign (n=1) and VUS (n=7). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Feb 02, 2024)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714835.3
First in ClinVar: Jun 15, 2021 Last updated: Feb 04, 2024 |
Comment:
PM2_supporting, PS3
Number of individuals with the variant: 3
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Uncertain significance
(Aug 02, 2023)
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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: SCV001173404.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.1731C>T variant (also known as p.Y577Y), located in coding exon 13 of the CFTR gene, results from a C to T substitution at nucleotide … (more)
The c.1731C>T variant (also known as p.Y577Y), located in coding exon 13 of the CFTR gene, results from a C to T substitution at nucleotide position 1731. This nucleotide substitution does not change the tyrosine at codon 577. Functional splicing assays have observed this variant to cause exon 12 skipping (exon 13 based on current exon numbering) using in vitro hybrid minigene transcripts, and authors suggested it may affect exonic splicing regulatory elements (Pagani F et al. Proc Natl Acad Sci U S A, 2005 May;102:6368-72; Fernandez Alanis E et al. Hum. Mol. Genet., 2012 Jun;21:2389-98; Donegà S et al. Hum Mutat, 2020 12;41:2143-2154). This alteration has been identified in multiple individuals diagnosed with pancreatitis (Nakano E et al. Dig Dis Sci, 2015 May;60:1297-307; Jalaly NY et al. Am J Gastroenterol, 2017 Aug;112:1320-1329). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001460201.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Rescue of common exon-skipping mutations in cystic fibrosis with modified U1 snRNAs. | Donegà S | Human mutation | 2020 | PMID: 32935393 |
An Evaluation of Factors Associated With Pathogenic PRSS1, SPINK1, CTFR, and/or CTRC Genetic Variants in Patients With Idiopathic Pancreatitis. | Jalaly NY | The American journal of gastroenterology | 2017 | PMID: 28440306 |
Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools. | Soukarieh O | PLoS genetics | 2016 | PMID: 26761715 |
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. | Ramalho AS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 25735457 |
Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. | Nakano E | Digestive diseases and sciences | 2015 | PMID: 25492507 |
Revertants, low temperature, and correctors reveal the mechanism of F508del-CFTR rescue by VX-809 and suggest multiple agents for full correction. | Farinha CM | Chemistry & biology | 2013 | PMID: 23890012 |
Functional analysis of synonymous substitutions predicted to affect splicing of the CFTR gene. | Scott A | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2012 | PMID: 22591852 |
An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. | Fernandez Alanis E | Human molecular genetics | 2012 | PMID: 22362925 |
Validation of high-resolution DNA melting analysis for mutation scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. | Audrezet MP | The Journal of molecular diagnostics : JMD | 2008 | PMID: 18687795 |
Reduced splicing efficiency induced by synonymous substitutions may generate a substrate for natural selection of new splicing isoforms: the case of CFTR exon 12. | Raponi M | Nucleic acids research | 2007 | PMID: 17172597 |
Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. | Pagani F | Proceedings of the National Academy of Sciences of the United States of America | 2005 | PMID: 15840711 |
Quantitative methods for the analysis of CFTR transcripts/splicing variants. | Amaral MD | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2004 | PMID: 15463919 |
New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12. | Pagani F | Human molecular genetics | 2003 | PMID: 12719375 |
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Text-mined citations for rs55928397 ...
HelpRecord last updated Jun 23, 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.