ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.2758G>A (p.Val920Met)
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.2758G>A (p.Val920Met)
Variation ID: 53561 Accession: VCV000053561.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117603632 (GRCh38) [ NCBI UCSC ] 7: 117243686 (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 Jan 25, 2018 Nov 20, 2023 Jun 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.2758G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Val920Met missense NC_000007.14:g.117603632G>A NC_000007.13:g.117243686G>A NG_016465.4:g.142849G>A LRG_663:g.142849G>A LRG_663t1:c.2758G>A LRG_663p1:p.Val920Met - Protein change
- V920M
- Other names
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- Canonical SPDI
- NC_000007.14:117603631:G:A
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 |
3598 | 4891 |
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 (7) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2022 | RCV000577642.19 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2022 | RCV000731224.23 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765926.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 26, 2023 | RCV000781291.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 20, 2022 | RCV003415801.4 |
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
(Nov 13, 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: SCV000788957.1
First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018 |
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Uncertain significance
(May 28, 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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Mendelics
Accession: SCV001137487.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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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: SCV001822121.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Jan 24, 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: SCV002750305.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.V920M variant (also known as c.2758G>A), located in coding exon 17 of the CFTR gene, results from a G to A substitution at nucleotide … (more)
The p.V920M variant (also known as c.2758G>A), located in coding exon 17 of the CFTR gene, results from a G to A substitution at nucleotide position 2758. The valine at codon 920 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in multiple individuals with CFTR-related disorders, including recurrent pancreatitis, congenital bilateral absence of the vas deferens, and disseminated bronchiectasis; however, complete genotype information was not provided (Bernardino AL et al. JOP, 2003 Sep;4:169-77; Amato F et al. J Mol Diagn, 2012 Jan;14:81-9). This amino acid position is highly conserved in available vertebrate species. 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)
Number of individuals with the variant: 1
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Uncertain significance
(Oct 23, 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: SCV002141106.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 920 of the CFTR protein (p.Val920Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 920 of the CFTR protein (p.Val920Met). This variant is present in population databases (rs373885282, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with cystic fibrosis, congenital absence of the vas deferens, and idiopathic pancreatitis (PMID: 10923036, 14526128, 23951356). ClinVar contains an entry for this variant (Variation ID: 53561). 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
(Sep 19, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885175.4
First in ClinVar: Dec 16, 2018 Last updated: Mar 04, 2023 |
Comment:
The CFTR c.2758G>A; p.Val920Met variant (rs373885282) is reported in the literature in the compound heterozygous state with a second pathogenic or pathogenic-mild variant in individuals … (more)
The CFTR c.2758G>A; p.Val920Met variant (rs373885282) is reported in the literature in the compound heterozygous state with a second pathogenic or pathogenic-mild variant in individuals affected with cystic fibrosis or CFTR-related disorders (see link to cystic fibrosis mutation database, Claustres 2000, Cohn 2005, Trujillano 2013). However, this variant is also reported in individuals affected with CFTR-related disorders in the heterozygous state without a second pathogenic variant (Amato 2012, Bernardino 2003, Rene 2011), or with other variants that potentially explain the phenotype (Groman 2002, Masson 2013). This variant is reported in ClinVar (Variation ID: 53561), and is found in the general population with an overall allele frequency of 0.013% (36/282810 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at codon 920 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.792). Due to conflicting information, the clinical significance of the p.Val920Met variant is uncertain at this time. References: Link to cystic fibrosis mutation database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=398 Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012 Jan;14(1):81-9. PMID: 22020151. Bernardino AL et al. CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients. JOP. 2003 Sep;4(5):169-77. PMID: 14526128. Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. PMID: 10923036. Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7. PMID: 16134171. Groman JD et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002 Aug 8;347(6):401-7. PMID: 12167682. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. PMID: 23951356. Rene C et al. p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. Eur J Hum Genet. 2011 Jan;19(1):36-42. PMID: 20717170. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013 Jul;50(7):455-62. PMID: 23687349. (less)
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Uncertain significance
(Sep 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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CFTR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108847.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CFTR c.2758G>A variant is predicted to result in the amino acid substitution p.Val920Met. This variant was observed in the compound heterozygous state with p.F508del … (more)
The CFTR c.2758G>A variant is predicted to result in the amino acid substitution p.Val920Met. This variant was observed in the compound heterozygous state with p.F508del in a patient with congenital absence of the vas deferens and another patient with non-classic CF (Claustres et al. 2000. PubMed ID: 10923036). The c.2758G>A (p.Val920Met) variant has also been reported alongside a 5T/13TG allele (phase not specified) in a patient with a CFTR-related disorder (Trujillano et al. 2013. PubMed ID: 23687349 and Trujillano et al. 2015. PubMed ID: 26436105), in trans with a variant of uncertain significance in a patient with chronic pancreatitis (Cohn et al. 2005. PubMed ID: 16134171), and in affected individuals with other variants that potentially explain the phenotype (Groman et al. 2002. PubMed ID: 12167682; Masson et al. 2013. PubMed ID: 23951356). This variant is also reported in the heterozygous state without a second pathogenic variant in patients affected with CFTR-related disorders (Amato et al. 2012. PubMed ID: 22020151; René et al. 2011. PubMed ID: 20717170; de Becdelièvre et al. 2011. PubMed ID: 21184098) but was seen in the heterozygous state in a healthy control individual (Steiner et al. 2011. PubMed ID: 21520337). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jan 08, 2018)
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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: SCV000859011.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pancreatitis
Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000897346.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Sep 28, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002540902.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Uncertain significance
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001986040.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with CFTR-related disorders such as pancreatitis and bronchiectasis (Bernardino … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with CFTR-related disorders such as pancreatitis and bronchiectasis (Bernardino 2003, Cohn 2005, Amato 2012); Observed with a pathogenic variant in individuals with cystic fibrosis, non-classic cystic fibrosis, and congenital absense of vas deferens in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Claustres 2000, Groman 2002); This variant is associated with the following publications: (PMID: 15241793, 16134171, 22020151, 14526128, 25087612, 9881185, 20717170, 20021716, 21184098, 26436105, 28603918, 20059485, 23951356, 12167682, 10923036, 33083013) (less)
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Uncertain significance
(Jun 26, 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: SCV000919204.4
First in ClinVar: Jun 02, 2019 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CFTR c.2758G>A (p.Val920Met) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded … (more)
Variant summary: CFTR c.2758G>A (p.Val920Met) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 252114 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than predicted for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. In a conservative assessment, c.2758G>A has been reported in the literature in individuals affected with Non-Classic Cystic Fibrosis, such as, in trans with p.F508del in CBAVD (n=1), CF (n=1) (Claustres_2000), with p.F508del and the 5T allele, phase non specified in non-classic CF (n=1) (Groman_2002), in trans with another VUS in sporadic ICP (n=1) (Cohn_2005), heterozygous in a healthy control individual (Steiner_2011), with another CTRC gene variant (p.Ala73Thr) of unknown pathogenicity in an individual with non specified ICP (Mason_2013), a case of hyperechogenic fetal bowel with a non-informative genotype (Rene_2011 and deBecdelievre_2011), as an isolated variant in two patients with CFTR-RD (Amato_2012), and with CFTR 5T-TG(13) allele, phase not specified in another patient with CFTR-RD (Trujillano_2013 and Trujillano_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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not provided
(-)
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no classification provided
Method: literature only
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CFTR-related disorders
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000679006.1
First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018 |
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Pathogenic
(-)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001424389.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility. | Cheema H | NPJ genomic medicine | 2020 | PMID: 33083013 |
Validation of a semiconductor next-generation sequencing assay for the clinical genetic screening of CFTR. | Trujillano D | Molecular genetics & genomic medicine | 2015 | PMID: 26436105 |
A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. | Masson E | PloS one | 2013 | PMID: 23951356 |
Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. | Trujillano D | Journal of medical genetics | 2013 | PMID: 23687349 |
Extensive molecular analysis of patients bearing CFTR-related disorders. | Amato F | The Journal of molecular diagnostics : JMD | 2012 | PMID: 22020151 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
Comprehensive description of CFTR genotypes and ultrasound patterns in 694 cases of fetal bowel anomalies: a revised strategy. | de Becdelièvre A | Human genetics | 2011 | PMID: 21184098 |
p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. | René C | European journal of human genetics : EJHG | 2011 | PMID: 20717170 |
Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. | Cohn JA | Human mutation | 2005 | PMID: 16134171 |
The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles. | Steiner B | Human mutation | 2004 | PMID: 15241793 |
CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients. | Bernardino AL | JOP : Journal of the pancreas | 2003 | PMID: 14526128 |
Variant cystic fibrosis phenotypes in the absence of CFTR mutations. | Groman JD | The New England journal of medicine | 2002 | PMID: 12167682 |
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. | Claustres M | Human mutation | 2000 | PMID: 10923036 |
Novel double mutant CF allele identified in a cystic fibrosis patient with meconium ileus. | Steffann J | Annales de genetique | 1998 | PMID: 9881185 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs373885282 ...
HelpRecord last updated Apr 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.