ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3200C>T (p.Ala1067Val)
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(1); Likely pathogenic(4); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3200C>T (p.Ala1067Val)
Variation ID: 53683 Accession: VCV000053683.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117611641 (GRCh38) [ NCBI UCSC ] 7: 117251695 (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 17, 2018 May 12, 2024 Mar 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3200C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ala1067Val missense NC_000007.14:g.117611641C>T NC_000007.13:g.117251695C>T NG_016465.4:g.150858C>T NG_056128.2:g.4695C>T LRG_663:g.150858C>T LRG_663t1:c.3200C>T LRG_663p1:p.Ala1067Val P13569:p.Ala1067Val - Protein change
- A1067V
- Other names
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- Canonical SPDI
- NC_000007.14:117611640:C: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 |
3704 | 5025 | |
LOC111674472 | - | - | - | GRCh38 | - | 387 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 18, 2023 | RCV000586398.17 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Nov 25, 2023 | RCV000670817.13 | |
CFTR-related disorder
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Likely pathogenic (1) |
no assertion criteria provided
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Apr 27, 2021 | RCV002228158.3 |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 19, 2024 | RCV004525827.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Nov 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000795720.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Jun 20, 2017)
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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: SCV000883571.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Comment:
The CFTR c.3200C>T; p.Ala1067Val variant (rs1800114) has been reported in an individual with congenital absence of vas deferens (CBAVD), who carries the severe pathogenic F508del … (more)
The CFTR c.3200C>T; p.Ala1067Val variant (rs1800114) has been reported in an individual with congenital absence of vas deferens (CBAVD), who carries the severe pathogenic F508del on the other chromosome (Jezequel 1995). Additionally, a different variant at this codon, p.Ala1067Pro, has been reported in an individual with CBAVD who also carries F508del (see database link), and a p.Ala1067Thr change has been reported in a cystic fibrosis (CF) patient with pancreatic insufficiency who also carries F508del (Ferec 1992). The p.Ala1067Thr variant was shown by functional analysis to have reduced CFTR maturation and chloride transport activity compared to wild type protein (Van Goor 2014). A fourth variant at this codon, p.Ala1067Asp, was found homozygously in a CF patient with mild pulmonary disease, and pancreatic insufficiency (see database link). The p.Ala1067Val variant is reported in ClinVar (Variation ID: 53683), and observed in general population databases at frequencies of 0.008 percent (1/13006 alleles, Exome Variant Server), and 0.001 percent (3/245722 alleles, Genome Aggregation Database). The alanine at codon 1067 is highly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Based on the above information, this variant is suspected to be mildly pathogenic. REFERENCES: Link to ClinVar database for p.Ala1067Val: https://www.ncbi.nlm.nih.gov/clinvar/variation/53683/ Link to SickKids database for p.Ala1067Pro: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1631 Link to SickKids database for p.Ala1067Asp: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1200 Ferec C et al. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet. 1992 Jun;1(3):188-91. Jezequel P et al. Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. Clin Chem. 1995 Jun;41(6 Pt 1):833-5. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36. (less)
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Uncertain significance
(Apr 27, 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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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507387.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
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Likely pathogenic
(Jul 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761731.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Jan 18, 2023)
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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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Revvity Omics, Revvity
Accession: SCV003818553.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001576971.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1067 of the CFTR protein (p.Ala1067Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1067 of the CFTR protein (p.Ala1067Val). This variant is present in population databases (rs1800114, gnomAD 0.003%). This missense change has been observed in individuals with congenital bilateral absence of the vas deferens and cystic fibrosis (PMID: 7539342, 7689902, 8556303; Invitae). ClinVar contains an entry for this variant (Variation ID: 53683). 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%. This variant disrupts the p.Ala1067 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 1284639, 8662892, 8702904, 23891399, 27131402), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 08, 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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Ambry Genetics
Accession: SCV002610235.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A1067V variant (also known as c.3200C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide … (more)
The p.A1067V variant (also known as c.3200C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3200. The alanine at codon 1067 is replaced by valine, an amino acid with similar properties. This variant has been detected in conjunction with a pathogenic CFTR mutation in individuals with congenital bilateral absence of the vas deferens (CBAVD), with no or few other signs of cystic fibrosis; however, the phase of the alterations (cis or trans) was not reported (De Braekeleer M et al. Mol. Hum. Reprod.,1996 Sep;2:669-77; Jézéquel P et al. Mol Hum Reprod, 2000 Dec;6:1063-7). Based on internal structural analysis, this variant is more destabilizing than known pathogenic variants within the domain (Jin MS et al. Nature, 2012 Oct;490:566-9). In our clinical cohort, this variant has been detected in trans with p.F508del in a newborn with normal sweat chloride levels. In addition, it has been detected by our laboratory in an individual homozygous for the p.F508del pathogenic mutation. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Mar 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696957.6
First in ClinVar: Mar 17, 2018 Last updated: May 12, 2024 |
Comment:
Variant summary: CFTR c.3200C>T (p.Ala1067Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein … (more)
Variant summary: CFTR c.3200C>T (p.Ala1067Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane 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 1.2e-05 in 250938 control chromosomes (gnomAD). c.3200C>T has been reported in the literature in the compound heterozygous state in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (e.g. Jezequel_1995, DeBraekeleer_1996, Woods_2013, Qu_2023). These data indicate that the variant is likely to be associated with disease. It was also reported as a non-informative genotype in a child with features of atypical CF and hypohydrotic ectodermal dysplasia (Welsh_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8556303, 9239681, 7539342, 11101688, 36604502, 25735457, 1284534, 24419263). ClinVar contains an entry for this variant (Variation ID: 53683). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Feb 11, 2016)
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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: SCV000339600.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Apr 27, 2021)
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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: SCV002507473.1
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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Correlation between CFTR variants and outcomes of ART in patients with CAVD in Central China. | Qu X | Scientific reports | 2023 | PMID: 36604502 |
Improving the Sensitivity and Positive Predictive Value in a Cystic Fibrosis Newborn Screening Program Using a Repeat Immunoreactive Trypsinogen and Genetic Analysis. | Sontag MK | The Journal of pediatrics | 2016 | PMID: 27131402 |
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 |
False-negative sweat chloride testing in a child with cystic fibrosis and undiagnosed hypohidrotic ectodermal dysplasia. | Welsh SK | Clinical pediatrics | 2014 | PMID: 24419263 |
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 |
Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. | Jin MS | Nature | 2012 | PMID: 23000902 |
Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations. | Jézéquel P | Molecular human reproduction | 2000 | PMID: 11101688 |
Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. | De Braekeleer M | Molecular human reproduction | 1996 | PMID: 9239681 |
Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. | Cotten JF | The Journal of biological chemistry | 1996 | PMID: 8702904 |
Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. | Seibert FS | The Journal of biological chemistry | 1996 | PMID: 8662892 |
Frequent occurrence of the CFTR intron 8 (TG)n 5T allele in men with congenital bilateral absence of the vas deferens. | Costes B | European journal of human genetics : EJHG | 1995 | PMID: 8556303 |
Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. | Jézéquel P | Clinical chemistry | 1995 | PMID: 7539342 |
A cluster of cystic fibrosis mutations in exon 17b of the CFTR gene: a site for rare mutations. | Mercier B | Journal of medical genetics | 1994 | PMID: 7529319 |
A rapid, efficient, and sensitive assay for simultaneous detection of multiple cystic fibrosis mutations. | Costes B | Human mutation | 1993 | PMID: 7689902 |
Detection of over 98% cystic fibrosis mutations in a Celtic population. | Férec C | Nature genetics | 1992 | PMID: 1284639 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
I:\T\Papers and Publications\CFTR\Alison Millson_ASHG_2013.pdf | - | - | - | - |
I:\T\Papers and Publications\CFTR\Woods A1067V.pdf | - | - | - | - |
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Text-mined citations for rs1800114 ...
HelpRecord last updated May 27, 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.