ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1673T>C (p.Leu558Ser)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.1673T>C (p.Leu558Ser)
Variation ID: 35829 Accession: VCV000035829.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117587827 (GRCh38) [ NCBI UCSC ] 7: 117227881 (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 Aug 31, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1673T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Leu558Ser missense NC_000007.14:g.117587827T>C NC_000007.13:g.117227881T>C NG_016465.4:g.127044T>C NG_056131.3:g.782T>C LRG_663:g.127044T>C LRG_663t1:c.1673T>C LRG_663p1:p.Leu558Ser P13569:p.Leu558Ser - Protein change
- L558S
- Other names
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- Canonical SPDI
- NC_000007.14:117587826: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
3821 | 5195 | |
LOC111674475 | - | - | - | GRCh38 | - | 145 |
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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Pathogenic (7) |
reviewed by expert panel
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Aug 31, 2018 | RCV000029483.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2019 | RCV001811199.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 18, 2023 | RCV003473128.1 |
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
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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Pathogenic
(Aug 31, 2018)
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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
Accession: SCV000924266.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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Pathogenic
(Feb 26, 2018)
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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: SCV000798106.1
First in ClinVar: Dec 12, 2017 Last updated: Dec 12, 2017 |
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Pathogenic
(Sep 12, 2019)
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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: SCV001470796.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The CFTR c.1673T>C; p.Leu558Ser variant (rs193922504) is reported in the literature in multiple patients with cystic fibrosis (Chavez-Saldana 2010, Sosnay 2013, CFTR2 database), or CBAVD … (more)
The CFTR c.1673T>C; p.Leu558Ser variant (rs193922504) is reported in the literature in multiple patients with cystic fibrosis (Chavez-Saldana 2010, Sosnay 2013, CFTR2 database), or CBAVD when found with a mild CFTR pathogenic variant (Li 2012). Functional analyses of the variant protein show a significant decrease in function (Raraigh 2018, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 35829), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 558 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010 62(6):546-52. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 11(4):316-23. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. (less)
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Pathogenic
(Feb 18, 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: SCV004213561.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 13, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001585583.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 558 of the CFTR protein (p.Leu558Ser). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 558 of the CFTR protein (p.Leu558Ser). This variant is present in population databases (rs193922504, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital bilateral absence of vas deferens and/or cystic fibrosis (PMID: 7525450, 9401110, 9439669, 10798368, 15638824, 22483971, 25910067). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35829). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 23974870). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 21, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052134.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
Comment:
Variant summary: CFTR c.1673T>C (p.Leu558Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) and AAA+ ATPase domain of … (more)
Variant summary: CFTR c.1673T>C (p.Leu558Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) and AAA+ ATPase domain 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 4e-06 in 251088 control chromosomes. c.1673T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Cystic Fibrosis (example, Kuwertz-Broking_1995, Dell Edera_2014, Dugueperoux_2005, Sosnay_2013, Kammesheidt_2006, Lucarelli_2013, Sanchez_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant reduction in CFTR maturation, though chloride conduction study was not performed (Sosnay_2013). Multiple clinical diagnostic laboratories, the CFTR-2 database and the CFTR-France database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 03, 2019)
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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: SCV001173154.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.L558S pathogenic mutation (also known as c.1673T>C and 1805T>C), located in coding exon 12 of the CFTR gene, results from a T to C … (more)
The p.L558S pathogenic mutation (also known as c.1673T>C and 1805T>C), located in coding exon 12 of the CFTR gene, results from a T to C substitution at nucleotide position 1673. The leucine at codon 558 is replaced by serine, an amino acid with dissimilar properties. This mutation has been reported in cystic fibrosis patients from Mexico, France, Italy, Spain, Latin America, and the Czech Republic (Orozco L, Hum. Genet. 2000 Mar; 106(3):360-5; Duguépéroux I, Eur. Respir. J. 2005 Mar; 25(3):468-73; Castaldo G, Ann. Hum. Genet. 2005 Jan; 69(Pt 1):15-24; Alonso MJ, Ann. Hum. Genet. 2007 Mar; 71(Pt 2):194-201; Pérez MM, J. Cyst. Fibros. 2007 May; 6(3):194-208; Kenková P, J. Cyst. Fibros. 2013 Sep; 12(5):532-7). In one study, functional assays demonstrated significantly reduced CFTR activity equal to 1.2% of wild-type levels (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). Based on the available evidence, p.L558S is classified as a pathogenic mutation. (less)
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Pathogenic
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169412.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Pathogenic
(Sep 07, 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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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001905500.1
First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
Comment:
Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
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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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Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. | Raraigh KS | American journal of human genetics | 2018 | PMID: 29805046 |
Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants. | Sánchez K | The application of clinical genetics | 2016 | PMID: 27022295 |
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 |
A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. | Lucarelli M | Molecular medicine (Cambridge, Mass.) | 2015 | PMID: 25910067 |
Analysis of cystic fibrosis gene mutations in children with cystic fibrosis and in 964 infertile couples within the region of Basilicata, Italy: a research study. | Dell'Edera D | Journal of medical case reports | 2014 | PMID: 25304080 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
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 |
Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. | Křenková P | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2013 | PMID: 23276700 |
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 |
CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. | Chávez-Saldaña M | Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion | 2010 | PMID: 21416780 |
Negative genetic neonatal screening for cystic fibrosis caused by compound heterozygosity for two large CFTR rearrangements. | Girardet A | Clinical genetics | 2007 | PMID: 17850636 |
Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. | Alonso MJ | Annals of human genetics | 2007 | PMID: 17331079 |
CFTR gene analysis in Latin American CF patients: heterogeneous origin and distribution of mutations across the continent. | Pérez MM | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2007 | PMID: 16963320 |
Comprehensive genetic analysis of the cystic fibrosis transmembrane conductance regulator from dried blood specimens--implications for newborn screening. | Kammesheidt A | Genetics in medicine : official journal of the American College of Medical Genetics | 2006 | PMID: 16980811 |
The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype. | Duguépéroux I | The European respiratory journal | 2005 | PMID: 15738290 |
Comprehensive cystic fibrosis mutation epidemiology and haplotype characterization in a southern Italian population. | Castaldo G | Annals of human genetics | 2005 | PMID: 15638824 |
Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy. | D'Apice MR | BMC medical genetics | 2004 | PMID: 15084222 |
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. | Claustres M | Human mutation | 2000 | PMID: 10923036 |
Spectrum of CFTR mutations in Mexican cystic fibrosis patients: identification of five novel mutations (W1098C, 846delT, P750L, 4160insGGGG and 297-1G-->A). | Orozco L | Human genetics | 2000 | PMID: 10798368 |
High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. | Casals T | Human genetics | 1997 | PMID: 9439669 |
CFTR gene analysis in cystic fibrosis patients: detection of 91% of molecular defects and identification of the novel mutation D979V. | Plouvier E | Annales de genetique | 1997 | PMID: 9401110 |
Haplotype analysis of 94 cystic fibrosis mutations with seven polymorphic CFTR DNA markers. | Morral N | Human mutation | 1996 | PMID: 8844213 |
Colchicine for secondary nephropathic amyloidosis in cystic fibrosis. | Kuwertz-Bröking E | Lancet (London, England) | 1995 | PMID: 7723568 |
Study of 12 mutations in Turkish cystic fibrosis patients. | Yilmaz E | Human heredity | 1995 | PMID: 7542223 |
Mutation analysis in 600 French cystic fibrosis patients. | Chevalier-Porst F | Journal of medical genetics | 1994 | PMID: 7525963 |
Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. | Dörk T | Human genetics | 1994 | PMID: 7525450 |
Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium. | Tsui LC | Human mutation | 1992 | PMID: 1284534 |
https://cftr2.org | - | - | - | - |
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Text-mined citations for rs193922504 ...
HelpRecord last updated Oct 08, 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.