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NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu)

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Interpretation:
drug response​

Review status:
reviewed by expert panel
Submissions:
7 (Most recent: Dec 31, 2020)
Last evaluated:
Mar 23, 2018
Accession:
VCV000053688.6
Variation ID:
53688
Description:
single nucleotide variant
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NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu)

Allele ID
68356
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7q31.2
Genomic location
7: 117611663 (GRCh38) GRCh38 UCSC
7: 117251717 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000007.13:g.117251717T>A
NC_000007.14:g.117611663T>A
NM_000492.4:c.3222T>A MANE Select NP_000483.3:p.Phe1074Leu missense
... more HGVS
Protein change
F1074L
Other names
-
Canonical SPDI
NC_000007.14:117611662:T:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (A)

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
1000 Genomes Project 0.00020
Links
ClinGen: CA327103
dbSNP: rs186045772
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
drug response 1 reviewed by expert panel Mar 23, 2018 RCV000660789.1
Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Dec 21, 2020 RCV000046829.5
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts May 23, 2018 RCV000522824.1
Likely pathogenic 1 criteria provided, single submitter - RCV001004302.1
Uncertain significance 1 criteria provided, single submitter Apr 3, 2020 RCV001289732.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CFTR - - GRCh38
GRCh37
1954 2699
LOC111674472 - - - GRCh38 - 233

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
drug response
(Mar 23, 2018)
reviewed by expert panel
Method: curation
ivacaftor response - Efficacy
Drug used for Cystic Fibrosis
Allele origin: germline
PharmGKB
Accession: SCV000783028.1
Submitted: (Jun 18, 2018)
Comment:
Drug is not necessarily used to treat response condition
Evidence details
Publications
PubMed (1)
Other databases
https://www.pharmgkb.org/clinica…
Comment:
PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or … (more)
Likely pathogenic
(Jul 11, 2014)
criteria provided, single submitter
Method: literature only
Cystic fibrosis
(Autosomal recessive inheritance)
Allele origin: unknown
Counsyl
Accession: SCV000220505.1
Submitted: (Mar 11, 2015)
Evidence details
Publications
PubMed (12)
Likely pathogenic
(May 23, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000861385.1
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Likely pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Allele origin: germline
Baylor Genetics
Accession: SCV001163179.1
Submitted: (Sep 27, 2019)
Evidence details
Likely pathogenic
(Dec 21, 2020)
criteria provided, single submitter
Method: clinical testing
Cystic fibrosis
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361660.2
Submitted: (Dec 31, 2020)
Evidence details
Publications
PubMed (17)
Comment:
Variant summary: CFTR c.3222T>A (p.Phe1074Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Uncertain significance
(Apr 03, 2020)
criteria provided, single submitter
Method: clinical testing
none provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
Accession: SCV001477710.1
Submitted: (Dec 11, 2020)
Evidence details
Comment:
The CFTR c.3222T>A; p.Phe1074Leu variant (rs186045772) is reported in the literature in individuals affected with CFTR-related disorders (CFTR-RD), such as pancreatitis, congenital bilateral absence of … (more)
Pathogenic
(Jul 13, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000617533.2
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The F1074L pathogenic variant in the CFTR gene has been reported previously in cis with the 5T allele in siblings with a mild cystic fibrosis … (more)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity. Prins S The Journal of biological chemistry 2020 PMID: 32934006
Patients with cystic fibrosis having a residual function mutation: Data from the Italian registry. Salvatore D Pediatric pulmonology 2019 PMID: 30561903
A New Targeted CFTR Mutation Panel Based on Next-Generation Sequencing Technology. Lucarelli M The Journal of molecular diagnostics : JMD 2017 PMID: 28736296
Newborn Screening for Cystic Fibrosis in California. Kharrazi M Pediatrics 2015 PMID: 26574590
Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. LaRusch J PLoS genetics 2014 PMID: 25033378
Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2. Zhou T Molecular cell 2014 PMID: 24813944
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
Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. Trujillano D Journal of medical genetics 2013 PMID: 23687349
Identification of the CFTR p.Phe508Del founder mutation in the absence of a polythymidine 9T allele in a Hispanic patient. Dharajiya N Clinical genetics 2013 PMID: 23017188
Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening. Kalid O Journal of computer-aided molecular design 2010 PMID: 20976528
Genetic testing in pancreatitis. Ooi CY Gastroenterology 2010 PMID: 20416310
Is early identification of asymptomatic infants with 'mild' CFTR genotypes clinically useful? Colombo C Acta paediatrica (Oslo, Norway : 1992) 2007 PMID: 17407489
Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Alonso MJ Annals of human genetics 2007 PMID: 17331079
Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Keiles S Pancreas 2006 PMID: 17003641
Identification of the 5T-12TG allele of the cystic fibrosis transmembrane conductance regulator gene in hypertrypsinaemic newborns. Padoan R Acta paediatrica (Oslo, Norway : 1992) 2006 PMID: 16801189
Atypical sinusitis in adults must lead to looking for cystic fibrosis and primary ciliary dyskinesia. Coste A The Laryngoscope 2004 PMID: 15126740
Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Casals T Human reproduction (Oxford, England) 2000 PMID: 10875853
High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Casals T Human genetics 1997 PMID: 9439669
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR - - - -
https://www.pharmgkb.org/clinicalAnnotation/1449191752 - - - -

Text-mined citations for rs186045772...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 14, 2021