ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.273+3A>C
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.273+3A>C
Variation ID: 35846 Accession: VCV000035846.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117509145 (GRCh38) [ NCBI UCSC ] 7: 117149199 (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 23, 2015 Feb 20, 2024 Mar 17, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.273+3A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000007.14:g.117509145A>C NC_000007.13:g.117149199A>C NG_016465.4:g.48362A>C NG_062452.1:g.783A>C LRG_663:g.48362A>C LRG_663t1:c.273+3A>C - Protein change
- Other names
- 405+3A->C
- Canonical SPDI
- NC_000007.14:117509144:A: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
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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Pathogenic (5) |
reviewed by expert panel
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Mar 17, 2017 | RCV000029501.15 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004421.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2023 | RCV003473133.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2022 | RCV003482230.1 |
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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Pathogenic
(Mar 17, 2017)
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reviewed by expert panel
Method: research
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR2
Study: CFTR2
Accession: SCV000245989.2 First in ClinVar: Sep 23, 2015 Last updated: Dec 12, 2017 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163465.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Likely pathogenic
(Jan 10, 2020)
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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: SCV002743647.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.273+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 3 in the CFTR gene. In one study, this … (more)
The c.273+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 3 in the CFTR gene. In one study, this variant was identified in two African American individuals with cystic fibrosis (CF) and it has been described as a common African American CF mutation (Macek M et al. Am. J. Hum. Genet., 1997 May;60:1122-7). In our internal cohort, this variant was identified with a known CF mutation in multiple diagnostic cases in our laboratory; however, the phase is not known (Ambry internal data). This nucleotide position is conserved in available vertebrate species. This variant was not reported in the gnomAD database, with coverage at this position. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. 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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Pathogenic
(May 04, 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: SCV004213514.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 07, 2022)
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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: SCV004228234.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
PP3, PM2, PM3_very_strong
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 04, 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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Invitae
Accession: SCV002288892.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional … (more)
This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 35846). This variant is also known as 405+3A>C. This variant has been observed in individuals with cystic fibrosis (PMID: 23974870). This sequence change falls in intron 3 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. It affects a nucleotide within the consensus splice site. (less)
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Likely pathogenic
(Dec 04, 2019)
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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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Myriad Genetics, Inc.
Accession: SCV001193953.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 9150159 and 11388756. Classification … (more)
NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 9150159 and 11388756. Classification of NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jun 19, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052152.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CFTR c.273+3A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: CFTR c.273+3A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict the variant weakens a canonical 5' donor site and one predicts it abolishes the site. In support of the predicted effect on splicing, Macek et al. point out that cytosine is the least common nucleotide at the +3 position of splice-donor sites, and that mutations at this location have been reported to cause aberrant RNA splicing (Macek_1997). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250744 control chromosomes (gnomAD). c.273+3A>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Macek_1997, Watson_2004, Dork_1998, Raraigh_2022, Bresnick_2021), and at least one family was reported as compound heterozygous with another pathogenic variant. In addition, the CFTR2 database reports 10 patients with this variant, stating that this variant causes CF when combined with another CF-causing variant (average sweat chloride levels in patients harboring this variant was found to be 109 mEq/L and 100% of these patients were pancreatic insufficient). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15371902, 15025720, 16049310, 9950364, 12089190, 20616359, 9150159, 21796730, 16244288, 11471192, 22975760, 26708955, 9683582, 34782259, 34857524). Four submitters, including an expert panel (CFTR2), have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (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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Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. | Raraigh KS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2022 | PMID: 34782259 |
Burden of cystic fibrosis in children <12 years of age prior to the introduction of CFTR modulator therapies. | Bresnick K | BMJ open respiratory research | 2021 | PMID: 34857524 |
Sequencing as a first-line methodology for cystic fibrosis carrier screening. | Beauchamp KA | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31036917 |
The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. | Schrijver I | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26708955 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme. | Berwouts S | Human mutation | 2011 | PMID: 21796730 |
The suitability of matrix assisted laser desorption/ionization time of flight mass spectrometry in a laboratory developed test using cystic fibrosis carrier screening as a model. | Farkas DH | The Journal of molecular diagnostics : JMD | 2010 | PMID: 20616359 |
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 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Characterization of publicly available lymphoblastoid cell lines for disease-associated mutations in 11 genes. | Bernacki SH | Clinical chemistry | 2005 | PMID: 16244288 |
Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations. | Schrijver I | The Journal of molecular diagnostics : JMD | 2005 | PMID: 16049310 |
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 |
Novel CFTR mutations in black cystic fibrosis patients. | Feuillet-Fieux MN | Clinical genetics | 2004 | PMID: 15025720 |
Development and evaluation of a PCR-based, line probe assay for the detection of 58 alleles in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. | Wang X | Clinical chemistry | 2002 | PMID: 12089190 |
Genetic markers of male infertility: Y chromosome microdeletions and cystic fibrosis transmembrane conductance gene mutations. | Sertić J | Croatian medical journal | 2001 | PMID: 11471192 |
Improved detection of cystic fibrosis mutations in the heterogeneous U.S. population using an expanded, pan-ethnic mutation panel. | Heim RA | Genetics in medicine : official journal of the American College of Medical Genetics | 2001 | PMID: 11388756 |
Cystic fibrosis carrier frequencies in populations of African origin. | Padoa C | Journal of medical genetics | 1999 | PMID: 9950364 |
Evidence for a common ethnic origin of cystic fibrosis mutation 3120+1G-->A in diverse populations. | Dörk T | American journal of human genetics | 1998 | PMID: 9683582 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. | Macek M Jr | American journal of human genetics | 1997 | PMID: 9150159 |
cftr2.org | - | - | - | - |
http://www.genet.sickkids.on.ca/ | - | - | - | - |
https://cftr2.org | - | - | - | - |
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Text-mined citations for rs74467662 ...
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.