ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1364C>A (p.Ala455Glu)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.1364C>A (p.Ala455Glu)
Variation ID: 7111 Accession: VCV000007111.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117548795 (GRCh38) [ NCBI UCSC ] 7: 117188849 (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 Mar 24, 2015 May 1, 2024 Mar 3, 2004 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1364C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ala455Glu missense NC_000007.14:g.117548795C>A NC_000007.13:g.117188849C>A NG_016465.4:g.88012C>A LRG_663:g.88012C>A LRG_663t1:c.1364C>A LRG_663p1:p.Ala455Glu P13569:p.Ala455Glu - Protein change
- A455E
- Other names
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- Canonical SPDI
- NC_000007.14:117548794:C: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.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00010
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 |
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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Pathogenic (11) |
practice guideline
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Mar 3, 2004 | RCV000007531.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763569.2 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV000660853.4 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004446.1 | |
Pathogenic (6) |
criteria provided, single submitter
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Apr 22, 2022 | RCV001530091.10 | |
CFTR-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Mar 17, 2017 | RCV001826427.1 |
Pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2023 | RCV003473003.1 |
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
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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pathogenic
(Mar 03, 2004)
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practice guideline
Method: curation
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Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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American College of Medical Genetics and Genomics (ACMG)
Study: The ACMG recommended carrier screening panel
Accession: SCV000071390.2 First in ClinVar: Jun 04, 2013 Last updated: Mar 24, 2015 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Mar 17, 2017)
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reviewed by expert panel
Method: research
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR2
Study: CFTR2
Accession: SCV000071495.4 First in ClinVar: Oct 18, 2013 Last updated: Dec 26, 2017 |
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drug response
Drug-variant association: Efficacy
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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ivacaftor response - Efficacy
Drug used for
Cystic Fibrosis
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV000783092.2
First in ClinVar: Jul 09, 2018 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
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Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163491.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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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: SCV001169478.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Pathogenic
(Nov 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194086.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000492.3(CFTR):c.1364C>A(A455E) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include … (more)
NM_000492.3(CFTR):c.1364C>A(A455E) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1364C>A(A455E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jul 24, 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: SCV001430619.1
First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020 |
Comment:
Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
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Pathogenic
(Jan 25, 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: SCV000074294.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the CFTR protein … (more)
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the CFTR protein (p.Ala455Glu). 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 individual(s) with cystic fibrosis (PMID: 2236053, 15371902, 23466340, 23974870). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7111). 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 function (PMID: 7542778, 23974870). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 16, 2017)
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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: SCV000696836.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The CFTR c.1364C>A (p.Ala455Glu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. … (more)
Variant summary: The CFTR c.1364C>A (p.Ala455Glu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by functional studies showing the variant to result in <10% chloride conductance (Sosnay_2013). This variant was found in 4/94982 control chromosomes at a frequency of 0.0000421, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous affected individuals in the literature and is a known common disease causing mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(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: SCV000894408.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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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: SCV000886236.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Pathogenic
(Apr 22, 2022)
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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: SCV001763938.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: reduced levels of mature CFTR protein and chloride transport compared to wildtype (Sheppard et al, 1995; VanGoor et … (more)
Published functional studies demonstrate a damaging effect: reduced levels of mature CFTR protein and chloride transport compared to wildtype (Sheppard et al, 1995; VanGoor et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21520337, 23420618, 7534226, 9402971, 32429104, 22975760, 25489051, 22658665, 23891399, 24440181, 23378603, 23974870, 20021716, 2236053, 18456578, 29261177, 10777368, 24416359, 7542778, 32204475, 31036917, 8886242, 22390181, 32848127) (less)
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Pathogenic
(Sep 21, 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: SCV004213371.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 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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Ambry Genetics
Accession: SCV002702901.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A455E pathogenic mutation (also known as c.1364C>A), located in coding exon 10 of the CFTR gene, results from a C to A substitution at … (more)
The p.A455E pathogenic mutation (also known as c.1364C>A), located in coding exon 10 of the CFTR gene, results from a C to A substitution at nucleotide position 1364. The alanine at codon 455 is replaced by glutamic acid, an amino acid with dissimilar properties. This mutation accounts for approximately 0.3% of cystic fibrosis (CF) alleles (Corvol H et al. Transl Res, 2016 Feb;168:40-9; Brennan ML et al. J Mol Diagn, 2016 Jan;18:3-14) and is typically associated with milder manifestations of CF (Bombieri C et al. Semin Respir Crit Care Med, 2015 Apr;36:180-93). Functional in vitro studies found that cells with this pathogenic mutation maintain 6.8% chloride conduction compared to wild-type (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Nov 01, 1990)
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no assertion criteria provided
Method: literature only
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CYSTIC FIBROSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027732.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 14, 2021 |
Comment on evidence:
In 2 chromosomes from patients with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a C-to-A change at nucleotide 1496 in exon 9 of … (more)
In 2 chromosomes from patients with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a C-to-A change at nucleotide 1496 in exon 9 of the CFTR gene that caused substitution of glutamic acid for alanine at position 455 (A455E). The exon in which the A455E mutation occurs has been corrected to exon 10; see, e.g., Vecchio-Pagan et al. (2016). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744709.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952962.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001806866.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927355.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964442.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Mar 17, 2017)
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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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Natera, Inc.
Accession: SCV002080580.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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GeneReviews
Accession: SCV001622787.2
First in ClinVar: May 23, 2021 Last updated: Oct 01, 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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Deep resequencing of CFTR in 762 F508del homozygotes reveals clusters of non-coding variants associated with cystic fibrosis disease traits. | Vecchio-Pagán B | Human genome variation | 2016 | PMID: 27917292 |
Cystic Fibrosis: A Review of Associated Phenotypes, Use of Molecular Diagnostic Approaches, Genetic Characteristics, Progress, and Dilemmas. | Brennan ML | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26631874 |
Translating the genetics of cystic fibrosis to personalized medicine. | Corvol H | Translational research : the journal of laboratory and clinical medicine | 2016 | PMID: 25940043 |
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 |
Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. | Van Goor F | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2014 | PMID: 23891399 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
CFTR2: How will it help care? | Castellani C | Paediatric respiratory reviews | 2013 | PMID: 23466340 |
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 |
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. | Gallati S | Reproductive biomedicine online | 2009 | PMID: 20021716 |
Molecular pathology of the CFTR locus in male infertility. | Claustres M | Reproductive biomedicine online | 2005 | PMID: 15705292 |
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. | Watson MS | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15371902 |
Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. | McKone EF | Lancet (London, England) | 2003 | PMID: 12767731 |
Two cystic fibrosis transmembrane conductance regulator mutations have different effects on both pulmonary phenotype and regulation of outwardly rectified chloride currents. | Fulmer SB | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7542778 |
Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. | Kerem BS | Proceedings of the National Academy of Sciences of the United States of America | 1990 | PMID: 2236053 |
https://cftr2.org | - | - | - | - |
https://www.pharmgkb.org/clinicalAnnotation/1449191649 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166162705 | - | - | - | - |
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Text-mined citations for rs74551128 ...
HelpRecord last updated May 19, 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.