ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1327G>T (p.Asp443Tyr)
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.
Pathogenic(8); Likely pathogenic(9); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.1327G>T (p.Asp443Tyr)
Variation ID: 53229 Accession: VCV000053229.68
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117548758 (GRCh38) [ NCBI UCSC ] 7: 117188812 (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 30, 2015 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1327G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Asp443Tyr missense NC_000007.14:g.117548758G>T NC_000007.13:g.117188812G>T NG_016465.4:g.87975G>T LRG_663:g.87975G>T LRG_663t1:c.1327G>T LRG_663p1:p.Asp443Tyr - Protein change
- D443Y
- Other names
- -
- Canonical SPDI
- NC_000007.14:117548757:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
The Genome Aggregation Database (gnomAD), exomes 0.00026
Exome Aggregation Consortium (ExAC) 0.00027
The Genome Aggregation Database (gnomAD) 0.00034
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
Help
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 |
3704 | 5025 | |
CFTR-AS1 | - | - | - | GRCh38 | - | 490 |
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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Conflicting interpretations of pathogenicity (11) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000046274.43 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Apr 1, 2024 | RCV000078976.44 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 5, 2014 | RCV000150335.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV001004444.9 | |
CFTR-related disorder
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Pathogenic (2) |
criteria provided, single submitter
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Mar 26, 2018 | RCV001009469.12 |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2023 | RCV003473449.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 23, 2021 | RCV002256030.9 |
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
(Apr 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800743.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Likely pathogenic
(Sep 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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CFTR-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000916180.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CFTR c.1327G>T (p.Asp443Tyr) missense variant has been reported in a compound heterozygous state in five individuals with chronic sinusitis and bronchitis and in a … (more)
The CFTR c.1327G>T (p.Asp443Tyr) missense variant has been reported in a compound heterozygous state in five individuals with chronic sinusitis and bronchitis and in a heterozygous state in one proband with congenital uni- or bilateral absence of the vas deferens (de Meeus et al. 1997; Mieusset et al. 2016). The p.Asp443Tyr variant has been reported as part of a complex allele, in cis with c.1727G>C (p.Gly576Ala) and c.2002C>T (p.Arg668Cys) in 57 probands in a compound heterozygous state and in three probands in a heterozygous state (El-Seedy et al. 2012; Abou Alaiwa et al. 2014). Abramowicz et al. (2000) reported the p.[Asp443Tyr;Gly576Ala;Arg668Cys] variant in a compound heterozygous state in a fetus with hyperechoic bowel, a sibling with a history of lower respiratory tract infection and slightly raised sweat chloride, and in an asymptomatic sibling. The p.[Asp443Tyr;Gly576Ala;Arg668Cys] complex allele has been reported in four of 1,423 controls. The p.Asp443Tyr variant is reported at a frequency of 0.000461 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies indicate that p.[Asp443Tyr;Gly576Ala;Arg668Cys] alters CFTR maturation and chloride conductance but retains some residual function, which is consistent with mild or moderate phenotypes. Based on the evidence, the p.Asp443Tyr variant is classified as likely pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 14, 2012)
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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: SCV000224838.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 4
Sex: mixed
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Uncertain significance
(Jun 05, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000197437.4
First in ClinVar: Jan 30, 2015 Last updated: Jan 30, 2015 |
Comment:
The Asp443Tyr variant in CFTR has been reported in >50 compound heterozygous ind ividuals with varying clinical diagnoses, including congenital bilateral absence of the van … (more)
The Asp443Tyr variant in CFTR has been reported in >50 compound heterozygous ind ividuals with varying clinical diagnoses, including congenital bilateral absence of the van deferens (CBAVD), diffuse bronchiectasis, idiopathic pancreatitis, a nd cystic fibrosis (de Meeus 1997, El-Seedy 2012); however most of these individ uals carried one or more CFTR variants in cis with this variant. This variant be en identified in 2/8588 European American and 2/4400 African American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs147422190). Functional data suggest that the Asp443Tyr variant may alter CFT R protein maturation (El-Seedy 2012), however this in vivo assay may not accurat ely reflect biological function. Computational prediction tools and evolutionary conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Asp443Tyr variant is uncertain. (less)
Number of individuals with the variant: 2
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Pathogenic
(Mar 26, 2018)
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criteria provided, single submitter
Method: curation
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CFTR-related disorders
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169564.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Likely pathogenic
(Aug 20, 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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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001431520.1
First in ClinVar: Sep 05, 2020 Last updated: Sep 05, 2020 |
Comment:
CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.
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Pathogenic
(Jul 17, 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: SCV000603073.3
First in ClinVar: Jan 30, 2015 Last updated: Jan 26, 2021 |
Comment:
The CFTR c.1327G>T; p.Asp443Tyr variant (rs147422190), is described in the literature in several individuals with CBAVD who carry a pathogenic severe variant on the opposite … (more)
The CFTR c.1327G>T; p.Asp443Tyr variant (rs147422190), is described in the literature in several individuals with CBAVD who carry a pathogenic severe variant on the opposite allele (de Meeus 1998). This variant is often associated with other variants in cis (G576A, R668C) as a complex allele, and as such is reported to cause a wide range of symptoms including individuals who are asymptomatic even with a pathogenic severe allele on the opposite chromosome, CBAVD, idiopathic pancreatitis, disseminated bronchiectasis, fetal bowel anomaly, and chronic sinus disease (El-Seedy 2012). This variant is classified as a variant of varying clinical consequences in the CFTR2 database (see link), and is reported in ClinVar (Variation ID: 53229). It is found in the general European population with an allele frequency of 0.05% (60/123724 alleles) in the Genome Aggregation Database, but may be a low quality site in this database. The aspartate at codon 443 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Based on available information, this variant is considered to be mildly pathogenic for CFTR-related disorders. References: CFTR2 database: https://cftr2.org de Meeus A et al. Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. Hum Mutat. 1998;11(6):480. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012 Nov;33(11):1557-65. (less)
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Pathogenic
(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: SCV001822047.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Mar 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002107092.2
First in ClinVar: Mar 19, 2022 Last updated: Apr 02, 2022 |
Comment:
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 22678879; 29805046) - PS3_supporting.The c.1327G>T;p.(Asp443Tyr) … (more)
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 22678879; 29805046) - PS3_supporting.The c.1327G>T;p.(Asp443Tyr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 53229; PMID: 21520337; PMID: 10922395; PMID: 22678879; PMID: 23951356; PMID: 15126740; PMID: 32512765; PMID: 32172930) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (ABC_tran) - PM1. The variant is present at low allele frequencies population databases (rs147422190 – gnomAD 0.002595%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asp443Tyr) was detected in trans with a pathogenic variant (PMID: 21520337) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 25133958; 20186691) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern - (PMID: 21520337) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Likely pathogenic
(Jul 09, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502708.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: yes
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Uncertain significance
(Oct 01, 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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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507374.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
|
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Uncertain significance
(Apr 23, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529672.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CFTR c.1327G>T (p.D443Y) variant has been reported in individuals with various CFTR-related diseases such as congenital bilateral absence of the vas deferens (CBAVD), idiopathic … (more)
The CFTR c.1327G>T (p.D443Y) variant has been reported in individuals with various CFTR-related diseases such as congenital bilateral absence of the vas deferens (CBAVD), idiopathic pancreatitis, diffuse bronchiectasis, fecal bowel anomalies, as well as healthy individuals. In many cases the variant was observed in cis with p.G576A and p.R668C (PMID: 10200050, 26946416, 32172930, 22678879). In silico tools suggest the impact of the variant on protein function is deleterious, though functional studies have only shown moderately decreased expression (PMID: 29805046, 22678879). This variant was observed in 60/123724 chromosomes in the European (Non-Finnish) population, with no homozygotes, according to the Genome Aggregation Database (PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 53229). Based on the current evidence available, this variant is unlikely to be causative of classic CF. However, its contribution to the development of a CFTR-related disorder as an isolated variant or as a component of the haplotype D443Y/G576A/R668C remains uncertain. Therefore, this variant is interpreted as a variant of uncertain significance. (less)
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Likely pathogenic
(Sep 05, 2022)
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criteria provided, single submitter
Method: curation
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002573806.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Comment:
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project … (more)
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_MOD, PM3_STR, PP3 (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Mendelics
Accession: SCV000886146.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Likely pathogenic
(Oct 31, 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
|
Baylor Genetics
Accession: SCV004211626.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
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Likely pathogenic
(Jul 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022522.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 29, 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: SCV000074287.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 443 of the CFTR protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 443 of the CFTR protein (p.Asp443Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in trans with a pathogenic variant in individuals affected with congenital absence of the vas deferens (CAVD) (PMID: 21520337). Additionally, this variant frequently occurs in cis with the missense variants p.Gly576Ala and p.Arg668Cys. This haplotype has been reported in individuals affected by CFTR-related diseases including CAVD, idiopathic chronic pancreatitis (ICP), chronic sinusitus, and bronchiectasis (PMID: 10922395, 21520337, 22678879, 23951356, 15126740). ClinVar contains an entry for this variant (Variation ID: 53229). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR protein function (PMID: 22678879). Furthermore, when this variant occurs in combination with p.Gly576Ala and p.Arg668Cys, CFTR chloride channel conductance is decreased. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250505.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
CFTR: PM3:Very Strong, PM2
Number of individuals with the variant: 4
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Likely 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
|
Baylor Genetics
Accession: SCV001163489.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
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Pathogenic
(Feb 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919136.3
First in ClinVar: Jun 02, 2019 Last updated: Sep 19, 2020 |
Comment:
Variant summary: CFTR c.1327G>T (p.Asp443Tyr) results in a non-conservative amino acid change located in the ABC transporter-like domain of the encoded protein sequence. Five of … (more)
Variant summary: CFTR c.1327G>T (p.Asp443Tyr) results in a non-conservative amino acid change located in the ABC transporter-like 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 0.00026 in 242986 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Classic or Non-Classic Cystic Fibrosis, allowing no conclusion about variant significance. This variant has also been reported to form a haplotype with two other variants, namely, c.1727G>C (p.Gly576Ala) and c.2002C>T (p.Arg668Cys). This complex haplotype c.[1327G>T;1727G>C;2002C>T] (p.[Asp443Tyr;Gly576Ala;Arg668Cys]), has been reported to be pathogenic for CFTR-RD. When ascertained conservatively for its occurrence in isolation, c.1327G>T alone (without the complex haplotype) has been reported in the literature in a compound heterozygous state with other pathogenic CFTR alleles in multiple individuals affected with features of sweat chloride positive classic Cystic Fibrosis, Non-classic Cystic Fibrosis such as CBAVD and settings of infertility (example, Claustres_2000, Steiner_2011, Viville_2000, Morea_2005). However, non-reporting of the other two variants that would constitute a complex allele in these reports cannot be entirely ruled out. Nevertheless, these data indicate that this variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function in isolation as well as part of the complex haplotype. The most pronounced isolated variant effect reports conflicting findings between studies ranging from no effect (El-Seedy_2012) to intermediate levels (Raraigh_2018) of chloride channel function (approximately 50% of WT levels) and a moderate alteration of CFTR maturation and localization (El-Seedy_2012). In one of these studies, the authors concluded that the combination of p.Gly576Ala and p.Arg668Cys affecting chloride channel activity coupled with p.Asp443Tyr effecting protein maturation would account for the pathogenicity of the overall haplotype (El-Seedy_2012). In contrast however, c.1727G>C and c.2002C>T have been reported as non-CF causing in isolation based on a large study evaluating the functional consequences of CFTR variants (Sosnay_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=2, Likely pathogenic, n=3, and VUS, n=1). Some of these submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant in isolation was classified as pathogenic for CFTR-related disorders. (less)
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Uncertain significance
(Jun 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601041.5
First in ClinVar: Mar 24, 2015 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported as part of a complex allele (PMIDs: 10601093 (1999), 10922395 (2000), 19812525 (2010), 26900683 (2016), and … (more)
In the published literature, this variant has been reported as part of a complex allele (PMIDs: 10601093 (1999), 10922395 (2000), 19812525 (2010), 26900683 (2016), and 32773111 (2020)) and observed in CFTR-Related disorders, mostly CBAVD and pancreatitis (PMIDs: 10200050 (1998), 10601093 (1999), 19812525 (2000), 15097853 (2004), 16126774 (2005), 17413420 (2007), 17975025 (2007), 17329263 (2007), 20100616 (2010), 21520337 (2011), 22678879 (2012), 23951356 (2013), 26990548 (2016), and 26946416 (2017)). In vitro functional studies have shown that this variant does not affect chloride channel activity, but it may affect CFTR protein maturation and subcellular localization (PMID: 22678879 (2012)). Another study indicates that this variant is associated with 53.2% of wild type CFTR function that may not be disease-causing (PMID: 29805046 (2018)). The frequency of this variant in the general population, 0.00048 (60/123724 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely pathogenic
(Jul 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001171326.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.D443Y variant (also known as c.1327G>T), located in coding exon 10 of the CFTR gene, results from a G to T substitution at nucleotide … (more)
The p.D443Y variant (also known as c.1327G>T), located in coding exon 10 of the CFTR gene, results from a G to T substitution at nucleotide position 1327. The aspartic acid at codon 443 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been described as part of a complex allele (p.[D443Y;G576A;R668C] or p.[D443Y;G576A]) in individuals with CFTR-related disorders, including congenital absence of the vas deferens (CAVD) and chronic pancreatitis; a second alteration was not always detected, nor phase (cis vs. trans) described (Bombieri C et al. J. Cyst. Fibros., 2011 Jun;10 Suppl 2:S86-102; Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20; Masson E et al. PLoS ONE, 2013 Aug;8:e73522). In vitro functional studies showed that this alteration affects protein maturation. In one study, p.D443Y showed decreased chloride channel activity when co-expressed with p.G576A and p.R668C, but not when expressed alone in cultured cells (El-Seedy et al. Hum Mutat. 2012; 33(11);15557-65). In another study, this variant showed decreased chloride channel activity when expressed alone (Raraigh KS et al. Am. J. Hum. Genet. 2018 Jun;102(6):1062-1077). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Oct 01, 2019)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507460.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
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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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Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges. | Bienvenu T | Genes | 2020 | PMID: 32512765 |
Variant classifications, databases and genotype-phenotype correlations. | Raynal C | Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | 2020 | PMID: 32172930 |
Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. | Raraigh KS | American journal of human genetics | 2018 | PMID: 29805046 |
The spectrum of renal involvement in male patients with infertility related to excretory-system abnormalities: phenotypes, genotypes, and genetic counseling. | Mieusset R | Journal of nephrology | 2017 | PMID: 26946416 |
NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine. | Abulí A | Human mutation | 2016 | PMID: 26990548 |
Genotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders. | Bombieri C | Seminars in respiratory and critical care medicine | 2015 | PMID: 25826586 |
Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. | Fogel BL | JAMA neurology | 2014 | PMID: 25133958 |
Neonates with cystic fibrosis have a reduced nasal liquid pH; a small pilot study. | Abou Alaiwa MH | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2014 | PMID: 24418186 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
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 |
Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. | Aissat A | Human mutation | 2013 | PMID: 23420618 |
CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. | El-Seedy A | Human mutation | 2012 | PMID: 22678879 |
Recommendations for the classification of diseases as CFTR-related disorders. | Bombieri C | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2011 | PMID: 21658649 |
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 |
Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. | Schneider A | Gastroenterology | 2011 | PMID: 20977904 |
ABPA in adulthood: a CFTR-related disorder. | Lebecque P | Thorax | 2011 | PMID: 20837875 |
Functional evaluation of paraplegin mutations by a yeast complementation assay. | Bonn F | Human mutation | 2010 | PMID: 20186691 |
Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? | Dorfman R | Clinical genetics | 2010 | PMID: 20059485 |
Independent contribution of common CFTR variants to chronic pancreatitis. | de Cid R | Pancreas | 2010 | PMID: 19812525 |
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. | Gallati S | Reproductive biomedicine online | 2009 | PMID: 20021716 |
Influence of the duplication of CFTR exon 9 and its flanking sequences on diagnosis of cystic fibrosis mutations. | El-Seedy A | The Journal of molecular diagnostics : JMD | 2009 | PMID: 19710401 |
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 |
Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. | Grangeia A | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17413420 |
Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. | Ratbi I | Human reproduction (Oxford, England) | 2007 | PMID: 17329263 |
Gender-sensitive association of CFTR gene mutations and 5T allele emerging from a large survey on infertility. | Morea A | Molecular human reproduction | 2005 | PMID: 16126774 |
A large-scale study of the random variability of a coding sequence: a study on the CFTR gene. | Modiano G | European journal of human genetics : EJHG | 2005 | PMID: 15536480 |
High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. | des Georges M | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2004 | PMID: 15698946 |
Rapid detection of CFTR gene rearrangements impacts on genetic counselling in cystic fibrosis. | Niel F | Journal of medical genetics | 2004 | PMID: 15520400 |
Atypical sinusitis in adults must lead to looking for cystic fibrosis and primary ciliary dyskinesia. | Coste A | The Laryngoscope | 2004 | PMID: 15126740 |
The phenotypic consequences of CFTR mutations. | Rowntree RK | Annals of human genetics | 2003 | PMID: 12940920 |
Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. | Pagani F | The Journal of biological chemistry | 2003 | PMID: 12732620 |
Prenatal detection of cystic fibrosis by ultrasonography: a retrospective study of more than 346 000 pregnancies. | Scotet V | Journal of medical genetics | 2002 | PMID: 12070257 |
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. | Claustres M | Human mutation | 2000 | PMID: 10923036 |
Fetal bowel hyperechogenicity may indicate mild atypical cystic fibrosis: a case associated with a complex CFTR allele. | Abramowicz MJ | Journal of medical genetics | 2000 | PMID: 10922395 |
Histological and genetic analysis and risk assessment for chromosomal aberration after ICSI for patients presenting with CBAVD. | Viville S | Human reproduction (Oxford, England) | 2000 | PMID: 10875876 |
Complete mutational screening of the cystic fibrosis transmembrane conductance regulator gene: cystic fibrosis mutations are not involved in healthy men with reduced sperm quality. | Pallares-Ruiz N | Human reproduction (Oxford, England) | 1999 | PMID: 10601093 |
Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. | de Meeus A | Human mutation | 1998 | PMID: 10200050 |
Molecular diagnosis of congenital bilateral absence of the vas deferens: analyses of the CFTR gene in 64 French patients. | Bienvenu T | Annales de genetique | 1997 | PMID: 9150843 |
Migraine headache--a long-term approach. | Shute WB | Zentralblatt fur Gynakologie | 1990 | PMID: 2267887 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs147422190 ...
HelpRecord last updated Jun 10, 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.