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.
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3208C>T (p.Arg1070Trp)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Drug response
Mar 2021 by
PharmGKB
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.3208C>T (p.Arg1070Trp)
Variation ID: 53685 Accession: VCV000053685.41
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117611649 (GRCh38) [ NCBI UCSC ] 7: 117251703 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 29, 2016 Oct 8, 2024 Mar 24, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.3208C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Arg1070Trp missense NC_000007.14:g.117611649C>T NC_000007.13:g.117251703C>T NG_016465.4:g.150866C>T NG_056128.2:g.4703C>T LRG_663:g.150866C>T LRG_663t1:c.3208C>T LRG_663p1:p.Arg1070Trp P13569:p.Arg1070Trp - Protein change
- R1070W
- Other names
- -
- Canonical SPDI
- NC_000007.14:117611648:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
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NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| CFTR | - | - |
GRCh38 GRCh37 |
3832 | 5210 | |
| LOC111674472 | - | - | - | GRCh38 | - | 403 |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 11, 2015 | RCV000219441.12 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000507471.17 | |
| drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV000660792.11 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 21, 2024 | RCV000757802.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 29, 2018 | RCV001009384.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 8, 2020 | RCV001731338.12 | |
| Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
Jun 6, 2024 | RCV002228159.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 30, 2023 | RCV002221194.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 28, 2024 | RCV003474570.2 |
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
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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|---|---|---|---|---|---|
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drug response
Drug-variant association: Efficacy
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
ivacaftor response - Efficacy
Drug used for
Cystic Fibrosis
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000783031.2
First in ClinVar: Jul 09, 2018 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
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
(Nov 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
CFTR-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000916186.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CFTR c.3208C>T (p.Arg1070Trp) missense variant is well described in the literature as a mild or intermediate variant and is reported to have varying clinical … (more)
The CFTR c.3208C>T (p.Arg1070Trp) missense variant is well described in the literature as a mild or intermediate variant and is reported to have varying clinical consequences including pancreatic sufficient cystic fibrosis (CF) and congenital bilateral absence of the vas deferens (CBAVD). The p.Arg1070Trp variant has been identified in a compound heterozygous state in at least four studies in six individuals with CBAVD (Jezequel et al. 1995; Mickle et al. 2000; Jezequel et al. 2000; Steiner et al. 2011). The variant has also been reported as part of a complex allele in a compound heterozygous state with a pathogenic splice site variant in a proband with CF (de Prada Merino et al. 2010). Functional studies by Van Goor et al. (2014) demonstrated the p.Arg1070Trp variant resulted in 8% of wild type levels of chloride ion transport. The p.Arg1070Trp variant is reported in the CFTR2 mutation database in a total of 13 alleles (Sosnay et al. 2013), and is described as a "mutation of varying clinical consequence." Incomplete penetrance is documented in association with the p.Arg1070Trp variant; not all individuals who carry this variant along with a second disease-causing CFTR variant in trans will display symptoms of a CFTR-related disorder (CFTR2 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg1070Trp variant is classified as 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
(May 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Congenital bilateral absence of vas deferens (Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271348.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Arg1070Trp variant in CFTR has been reported in >20 compound heterozygous individuals (the majority carrying p.Phe508del) primarily affected by milder for ms of CFTR-related … (more)
The p.Arg1070Trp variant in CFTR has been reported in >20 compound heterozygous individuals (the majority carrying p.Phe508del) primarily affected by milder for ms of CFTR-related disorders (congenital bilateral absence of the vas deferens a nd cystic fibrosis) and more than half of these individuals were reported to hav e normal to low sweat chloride levels (Jezequel 1995, Feldmann 2003, Krasnov 200 8, Pelletier 2010, de Prada Merino 2010, Steiner 2011, Sosnay 2013). In addition , this variant has been identified in 4/66100 of European chromosomes and 1/1034 0 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs202179988). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. In vitro functional studies provide some evidence that the p.Arg1070Trp variant may impact protein function (Krasnov 2008, Sosnay 2013, Van Goor 2014). However, these types of assays may not accurately represent biologi cal function. In summary, this variant meets our criteria to be classified as pa thogenic for CTFR-related disorders including CBAVD and cystic fibrosis in an au tosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) base d upon multiple co-occurrences with pathogenic variants and its low frequency in the general population. (less)
Number of individuals with the variant: 1
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163177.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
|
|
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Pathogenic
(Feb 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984011.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
Comment:
The p.Arg1070Trp variant in CFTR has been reported in trans with other pathogenic variants (mainly p.Phe508del) in several individuals affected by milder forms of CFTR-related … (more)
The p.Arg1070Trp variant in CFTR has been reported in trans with other pathogenic variants (mainly p.Phe508del) in several individuals affected by milder forms of CFTR-related disorders (congenital bilateral absence of the vas deferens and cystic fibrosis) many of whom had normal to low sweat chloride levels and were pancreatic sufficient7891011121314. This variant has also been identified in 14/282342 (0.005% 0 homozygotes) total alleles in the Genome Aggregation Database (gnomAD). This allele frequency is still low enough to be consistent with a recessive carrier frequency. In vitro functional studies provided evidence that the p.Arg1070Trp variant may impact protein function91315. This variant has been shown to respond to Ivacaftor treatment15. In summary this variant meets our criteria to be classified as pathogenic for milder forms of CF-related disease when in trans with other CF-causing variants. 7. Jézéquel P Dorval I Fergelot P Chauvel B Le Treut A Le Gall JY Le Lannou D Blayau M. Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. Clin Chem. 41(6):833-5. (1995). 8. Feldmann D Couderc R Audrezet MP Ferec C Bienvenu T Desgeorges M Claustres M Mittre H Blayau M Bozon D Malinge MC Monnier N Bonnefont JP Iron A Bieth E Dumur V Clavel C Cazeneuve C Girodon E. CFTR genotypes in patients with normal or borderline sweat chloride levels. Hum Mutat. 22(4):340. (2003). 9. Krasnov KV Tzetis M Cheng J Guggino WB Cutting GR. Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships. Hum Mutat. 29(11):1364-72. (2008). 10. Pelletier AL Bienvenu T Rebours V O'Toole D Hentic O Maire F Hammel P Ruszniewski P Lévy P. CFTR gene mutations in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 10(2-3):158-64. (2010). 11. de Prada Merino A Bütschi FN Bouchardy I Beckmann JS Morris MA Hafen GM Fellmann F. [R74WR1070WD1270N]: a new complex allele responsible for cystic fibrosis. J Cyst Fibros. 9(6):447-9. (2010). 12. Steiner B Rosendahl J Witt H Teich N Keim V Schulz HU Pfützer R Löhr M Gress TM Nickel R Landt O Koudova M Macek M Jr Farre A Casals T Desax MC Gallati S Gomez-Lira M Audrezet MP Férec C des Georges M Claustres M Truninger K. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 32(8):912-20. (2011). 13. Sosnay PR Siklosi KR Van Goor F Kaniecki K Yu H Sharma N Ramalho AS Amaral MD Dorfman R Zielenski J Masica DL Karchin R Millen L Thomas PJ Patrinos GP Corey M Lewis MH Rommens JM Castellani C Penland CM Cutting GR.Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct45(10):1160-7 (2013). 14. Clinial and functional translation of CFTR. CFTR2.org. 15. Van Goor F Yu H Burton B Hoffman BJ.Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. Jan13(1):29-36. (2014). 16. Ong T Marshall SG Karczeski BA et al. Cystic Fibrosis and Congenital Absence of the Vas Deferens. 2001 Mar 26 [Updated 2017 Feb 2]. In: Adam MP Ardinger HH Pagon RA et al. editors. GeneReviews® [Internet]. Seattle (WA): University of Washington Seattle 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1250/. 17. den Dunnen J. T. et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum. Mutat. 37 564–569 (2016). 18. Richards S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17 405–24 (2015). (less)
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Pathogenic
(Dec 22, 2020)
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criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002507333.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
|
|
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Pathogenic
(Nov 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: yes
Allele origin:
unknown
|
Mendelics
Accession: SCV000886268.2
First in ClinVar: Feb 18, 2019 Last updated: Dec 11, 2022 |
|
|
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Pathogenic
(Oct 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001180561.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.R1070W pathogenic mutation (also known as c.3208C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at … (more)
The p.R1070W pathogenic mutation (also known as c.3208C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3208. The arginine at codon 1070 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this mutation was identified in conjunction with a second CFTR alteration in 24 individuals with pancreatic sufficient cystic fibrosis or congenital bilateral absence of the vas deferens (CBAVD) (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72). In vitro functional studies showed that cells with this mutation have significantly decreased chloride conductance compared to wild type (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36) and CFTR protein with this mutation was able to process into mature protein but with decreased efficiency compared to wild-type (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72). The p.R1070W alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Mar 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004213302.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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pathogenic
(Dec 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601093.3
First in ClinVar: Sep 30, 2017 Last updated: Sep 29, 2024 |
Comment:
In the published literature, the variant has been reported in several individuals affected with CBAVD or non-classic CF (PMID: 18951463 (2008), 20880762 (2010), 21520337 (2011), … (more)
In the published literature, the variant has been reported in several individuals affected with CBAVD or non-classic CF (PMID: 18951463 (2008), 20880762 (2010), 21520337 (2011), 26708955 (2016)). In addition, in vitro functional studies show this variant has a deleterious effect on CFTR protein processing, localization, and function (PMID: 18951463 (2008), 23974870 (2013), 23891399 (2014)). However, it was observed to have high chloride channel function in an earlier study (PMID: 10762539 (2000)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 29, 2018)
|
criteria provided, single submitter
Method: curation
|
cystic fibrosis
CFTR-related disorders
Affected status: yes
Allele origin:
germline
|
CFTR-France
Accession: SCV001169237.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
|
|
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Pathogenic
(Jun 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917197.4
First in ClinVar: Jun 02, 2019 Last updated: Aug 08, 2022 |
Comment:
Variant summary: CFTR c.3208C>T (p.Arg1070Trp) 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.3208C>T (p.Arg1070Trp) 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 4.8e-05 in 250962 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3208C>T has been reported in the literature in compound heterozygosity with another pathogenic variant in multiple individuals affected with CFTR-Related Diseases, primarily CBAVD (e.g. Jezequel_1995, Steiner_2011) and Non-Classic Cystic Fibrosis (e.g. McGinnis_2005, Sosnay_2013). These data indicate that the variant is likely to be associated with disease. A worldwide survey of patients with the p.Arg1070Trp variant identified 24 patients with complete clinical data (21 of which had the common pathogenic variant p.Phe508del or another severe CFTR mutation), and included 15 patients with CBAVD, 9 with non-classic CF, and 1 with classic CF phenotypes (Krasnov_2008). A second large survey that collected data from CF registries and clinics in the US and Europe reported the variant in a total of 13 CF alleles, but indicated that only 20% of the individuals were pancreatic-insufficient, with a mean lung function of 93.7%. 16.7% of these patients had tested positive for Pseudomonas (Sosnay_2013). Collectively, the clinical data on patients with this variant suggests that c.3208C>T is most likely a relatively mild mutation that is most often associated with either pancreatic-sufficient non-classic CF or CBAVD when present in trans with a more severe CFTR mutation. Several functional studies evaluating an impact on protein function have reported conflicting conclusions regarding the effects of this variant. One study reported that chloride channel function in cells expressing the variant was comparable to wild-type (e.g. Mickle_2000), however, it has also been reported that chloride conductance in cells expressing the variant was <10% that of wild-type (e.g. Van Goor_2013, Sosnay_2013). CFTR maturation and the amount of protein expression was 91% and 67.8% of the wild-type as measured in HeLa cells and FRT cells, respectively (Sosnay_2013), and the variant was reported to retain localization to the apical membrane, albeit less efficiently than the wild-type protein (e.g. Krasnov_2008). Eleven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified teh variant VUS (n=1), likely pathogenic (n=1) and pathogenic (n=9). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Dec 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002762511.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
Published functional studies demonstrate a damaging effect: reduced cell surface expression and chloride transport with defective channel gating (Seibert et al., 1996; Sosnay et al., … (more)
Published functional studies demonstrate a damaging effect: reduced cell surface expression and chloride transport with defective channel gating (Seibert et al., 1996; Sosnay et al., 2013; VanGoor et al., 2014); Observed with a pathogenic variant in patients with cystic fibrosis or CFTR-related disorders (Jezequel et al., 2000; McGinniss et al., 2005; Krasnov et al., 2008; Lebecque et al., 2011; Baldwin et al., 2019); 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: 8530001, 31036917, 27171515, 30873022, 25087612, 21520337, 23891399, 20460946, 21228398, 27469177, 8662892, 18951463, 10762539, 23974870, 7539342, 26708955, 20837875, 17331079, 11101688, 26014425, 16189704, 12955726, 12815607, 20880762, 35327663, 31268981, 34996830, 33374015, 35451201) (less)
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Pathogenic
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001580624.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1070 of the CFTR protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1070 of the CFTR protein (p.Arg1070Trp). This variant is present in population databases (rs202179988, gnomAD 0.01%). This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferens (PMID: 7539342, 10923036, 12167682, 15070876). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53685). 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: 18951463, 23891399). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800290.3
First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.3208C>T; p.Arg1070Trp variant (rs202179988) is reported in the literature in dozens of individuals affected with cystic fibrosis (CF) or other CFTR-related disorders (Jezequel … (more)
The CFTR c.3208C>T; p.Arg1070Trp variant (rs202179988) is reported in the literature in dozens of individuals affected with cystic fibrosis (CF) or other CFTR-related disorders (Jezequel 1995, Krasnov 2008, Sosnay 2013, CFTR2 database). Most patients carrying p.Arg1070Trp and a second CF-causing variant exhibit non-classic CF or milder symptoms such as congenital absence of the vas deferens or pancreatitis, although a minority of patients are reported with pancreatic-insufficient CF (Krasnov 2008, CFTR2 database). Functional studies suggest p.Arg1070 affects CFTR function and reduces chloride transport activity (Van Goor 2014). This variant is reported as likely pathogenic or pathogenic in ClinVar (Variation ID: 53685), and it is found in the general population with an overall frequency of 0.005% (14/282342 alleles) in the Genome Aggregation Database. Additionally, other amino acid substitutions at this codon (p.Arg1070Gln, p.Arg1070Pro) have been reported in individuals with CF or CFTR-related disorders and are considered disease-causing (Krasnov 2008, Sosnay 2013, CFTR2 database). Based on available information, the p.Arg1070Trp variant is considered to be pathogenic with varying clinical consequences. References: CFTR2 database: http://cftr2.org/ 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. Krasnov KV et al. Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships. Hum Mutat. 2008 Nov;29(11):1364-72. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. 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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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral absence of vas deferens
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002498618.2
First in ClinVar: Apr 12, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace arginine with tryptophan at codon 1070 of the CFTR protein, p.(Arg1070Trp). The arginine residue is evolutionarily conserved (100 … (more)
This sequence change is predicted to replace arginine with tryptophan at codon 1070 of the CFTR protein, p.(Arg1070Trp). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the fourth cytoplasmic loop of the cystic fibrosis transmembrane (CL4). There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.005%, which is consistent with recessive disease (rs202179988, 14/282,342 alleles, 0 homozygotes in gnomAD v2.1). It is classified as a CFTR variant of varying clinical consequences, and has been identified with a second pathogenic allele (mainly p.Phe508del) in non-classic pancreatic cystic fibrosis (CF), congenital bilateral absence of the vas deferens, and recurrent pancreatitis (for example PMID: 18951463, 31268981). The variant has also been identified as part of a complex allele that causes classic CF, when found in trans with a second pathogenic variant (PMID: 20880762). In vitro functional assays demonstrate that the variant causes mild defects on chloride transport and is inserted into the apical membrane at reduced levels (PMID: 8662892, 18951463, 23891399). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Additionally, there is a different missense change (p.Arg1070Gln) at the same position determined to be pathogenic (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM5, PS3_Supporting, PM2_Supporting, PP3. (less)
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Pathogenic
(Dec 22, 2020)
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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: SCV002507417.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
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Likely pathogenic
(Jun 06, 2024)
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no assertion criteria provided
Method: clinical testing
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CFTR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004113344.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The CFTR c.3208C>T variant is predicted to result in the amino acid substitution p.Arg1070Trp. This variant has been reported in cohorts of individuals with suspected … (more)
The CFTR c.3208C>T variant is predicted to result in the amino acid substitution p.Arg1070Trp. This variant has been reported in cohorts of individuals with suspected cystic fibrosis (see, for example, Krasnov et al. 2008. PubMed ID: 18951463; Pelletier et al. 2010. PubMed ID: 20460946; Ferec et al. 1995. PubMed ID: 8530001) as well as in the compound heterozygous state in patients with congenital bilateral absence of vas deferens (Jezequel et al. 1995. PubMed ID: 7539342; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies suggest that this variant results in a defect of normal CFTR processing (Van Goor et al. 2013. PubMed ID: 23891399; Sosnay et al. 2013. PubMed ID: 23974870), with at least one study suggesting that the p.Arg1070Trp variant may be a more mildly deleterious allele (Krasnov et al. 2008. PubMed ID: 18951463). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Dec 26, 2018)
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no assertion criteria provided
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132151.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Comment:
Comment:
The CFTR c.3208C>T (p.Arg1070Trp) missense variant is well described in the literature as a mild or intermediate variant and is reported to have varying clinical consequences including pancreatic sufficient cystic fibrosis (CF) and congenital bilateral absence of the vas deferens (CBAVD). The p.Arg1070Trp variant has been identified in a compound heterozygous state in at least four studies in six individuals with CBAVD (Jezequel et al. 1995; Mickle et al. 2000; Jezequel et al. 2000; Steiner et al. 2011). The variant has also been reported as part of a complex allele in a compound heterozygous state with a pathogenic splice site variant in a proband with CF (de Prada Merino et al. 2010). Functional studies by Van Goor et al. (2014) demonstrated the p.Arg1070Trp variant resulted in 8% of wild type levels of chloride ion transport. The p.Arg1070Trp variant is reported in the CFTR2 mutation database in a total of 13 alleles (Sosnay et al. 2013), and is described as a "mutation of varying clinical consequence." Incomplete penetrance is documented in association with the p.Arg1070Trp variant; not all individuals who carry this variant along with a second disease-causing CFTR variant in trans will display symptoms of a CFTR-related disorder (CFTR2 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg1070Trp variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The p.Arg1070Trp variant in CFTR has been reported in >20 compound heterozygous individuals (the majority carrying p.Phe508del) primarily affected by milder for ms of CFTR-related disorders (congenital bilateral absence of the vas deferens a nd cystic fibrosis) and more than half of these individuals were reported to hav e normal to low sweat chloride levels (Jezequel 1995, Feldmann 2003, Krasnov 200 8, Pelletier 2010, de Prada Merino 2010, Steiner 2011, Sosnay 2013). In addition , this variant has been identified in 4/66100 of European chromosomes and 1/1034 0 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs202179988). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. In vitro functional studies provide some evidence that the p.Arg1070Trp variant may impact protein function (Krasnov 2008, Sosnay 2013, Van Goor 2014). However, these types of assays may not accurately represent biologi cal function. In summary, this variant meets our criteria to be classified as pa thogenic for CTFR-related disorders including CBAVD and cystic fibrosis in an au tosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) base d upon multiple co-occurrences with pathogenic variants and its low frequency in the general population.
Comment:
The p.R1070W pathogenic mutation (also known as c.3208C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3208. The arginine at codon 1070 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this mutation was identified in conjunction with a second CFTR alteration in 24 individuals with pancreatic sufficient cystic fibrosis or congenital bilateral absence of the vas deferens (CBAVD) (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72). In vitro functional studies showed that cells with this mutation have significantly decreased chloride conductance compared to wild type (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36) and CFTR protein with this mutation was able to process into mature protein but with decreased efficiency compared to wild-type (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72). The p.R1070W alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
In the published literature, the variant has been reported in several individuals affected with CBAVD or non-classic CF (PMID: 18951463 (2008), 20880762 (2010), 21520337 (2011), 26708955 (2016)). In addition, in vitro functional studies show this variant has a deleterious effect on CFTR protein processing, localization, and function (PMID: 18951463 (2008), 23974870 (2013), 23891399 (2014)). However, it was observed to have high chloride channel function in an earlier study (PMID: 10762539 (2000)). Based on the available information, this variant is classified as pathogenic.
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Comment:
Variant summary: CFTR c.3208C>T (p.Arg1070Trp) 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 4.8e-05 in 250962 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3208C>T has been reported in the literature in compound heterozygosity with another pathogenic variant in multiple individuals affected with CFTR-Related Diseases, primarily CBAVD (e.g. Jezequel_1995, Steiner_2011) and Non-Classic Cystic Fibrosis (e.g. McGinnis_2005, Sosnay_2013). These data indicate that the variant is likely to be associated with disease. A worldwide survey of patients with the p.Arg1070Trp variant identified 24 patients with complete clinical data (21 of which had the common pathogenic variant p.Phe508del or another severe CFTR mutation), and included 15 patients with CBAVD, 9 with non-classic CF, and 1 with classic CF phenotypes (Krasnov_2008). A second large survey that collected data from CF registries and clinics in the US and Europe reported the variant in a total of 13 CF alleles, but indicated that only 20% of the individuals were pancreatic-insufficient, with a mean lung function of 93.7%. 16.7% of these patients had tested positive for Pseudomonas (Sosnay_2013). Collectively, the clinical data on patients with this variant suggests that c.3208C>T is most likely a relatively mild mutation that is most often associated with either pancreatic-sufficient non-classic CF or CBAVD when present in trans with a more severe CFTR mutation. Several functional studies evaluating an impact on protein function have reported conflicting conclusions regarding the effects of this variant. One study reported that chloride channel function in cells expressing the variant was comparable to wild-type (e.g. Mickle_2000), however, it has also been reported that chloride conductance in cells expressing the variant was <10% that of wild-type (e.g. Van Goor_2013, Sosnay_2013). CFTR maturation and the amount of protein expression was 91% and 67.8% of the wild-type as measured in HeLa cells and FRT cells, respectively (Sosnay_2013), and the variant was reported to retain localization to the apical membrane, albeit less efficiently than the wild-type protein (e.g. Krasnov_2008). Eleven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified teh variant VUS (n=1), likely pathogenic (n=1) and pathogenic (n=9). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies demonstrate a damaging effect: reduced cell surface expression and chloride transport with defective channel gating (Seibert et al., 1996; Sosnay et al., 2013; VanGoor et al., 2014); Observed with a pathogenic variant in patients with cystic fibrosis or CFTR-related disorders (Jezequel et al., 2000; McGinniss et al., 2005; Krasnov et al., 2008; Lebecque et al., 2011; Baldwin et al., 2019); 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: 8530001, 31036917, 27171515, 30873022, 25087612, 21520337, 23891399, 20460946, 21228398, 27469177, 8662892, 18951463, 10762539, 23974870, 7539342, 26708955, 20837875, 17331079, 11101688, 26014425, 16189704, 12955726, 12815607, 20880762, 35327663, 31268981, 34996830, 33374015, 35451201)
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1070 of the CFTR protein (p.Arg1070Trp). This variant is present in population databases (rs202179988, gnomAD 0.01%). This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferens (PMID: 7539342, 10923036, 12167682, 15070876). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53685). 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: 18951463, 23891399). For these reasons, this variant has been classified as Pathogenic.
Comment:
The CFTR c.3208C>T; p.Arg1070Trp variant (rs202179988) is reported in the literature in dozens of individuals affected with cystic fibrosis (CF) or other CFTR-related disorders (Jezequel 1995, Krasnov 2008, Sosnay 2013, CFTR2 database). Most patients carrying p.Arg1070Trp and a second CF-causing variant exhibit non-classic CF or milder symptoms such as congenital absence of the vas deferens or pancreatitis, although a minority of patients are reported with pancreatic-insufficient CF (Krasnov 2008, CFTR2 database). Functional studies suggest p.Arg1070 affects CFTR function and reduces chloride transport activity (Van Goor 2014). This variant is reported as likely pathogenic or pathogenic in ClinVar (Variation ID: 53685), and it is found in the general population with an overall frequency of 0.005% (14/282342 alleles) in the Genome Aggregation Database. Additionally, other amino acid substitutions at this codon (p.Arg1070Gln, p.Arg1070Pro) have been reported in individuals with CF or CFTR-related disorders and are considered disease-causing (Krasnov 2008, Sosnay 2013, CFTR2 database). Based on available information, the p.Arg1070Trp variant is considered to be pathogenic with varying clinical consequences. References: CFTR2 database: http://cftr2.org/ 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. Krasnov KV et al. Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships. Hum Mutat. 2008 Nov;29(11):1364-72. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. 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.
Comment:
This sequence change is predicted to replace arginine with tryptophan at codon 1070 of the CFTR protein, p.(Arg1070Trp). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the fourth cytoplasmic loop of the cystic fibrosis transmembrane (CL4). There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.005%, which is consistent with recessive disease (rs202179988, 14/282,342 alleles, 0 homozygotes in gnomAD v2.1). It is classified as a CFTR variant of varying clinical consequences, and has been identified with a second pathogenic allele (mainly p.Phe508del) in non-classic pancreatic cystic fibrosis (CF), congenital bilateral absence of the vas deferens, and recurrent pancreatitis (for example PMID: 18951463, 31268981). The variant has also been identified as part of a complex allele that causes classic CF, when found in trans with a second pathogenic variant (PMID: 20880762). In vitro functional assays demonstrate that the variant causes mild defects on chloride transport and is inserted into the apical membrane at reduced levels (PMID: 8662892, 18951463, 23891399). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Additionally, there is a different missense change (p.Arg1070Gln) at the same position determined to be pathogenic (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM5, PS3_Supporting, PM2_Supporting, PP3.
Comment:
The CFTR c.3208C>T variant is predicted to result in the amino acid substitution p.Arg1070Trp. This variant has been reported in cohorts of individuals with suspected cystic fibrosis (see, for example, Krasnov et al. 2008. PubMed ID: 18951463; Pelletier et al. 2010. PubMed ID: 20460946; Ferec et al. 1995. PubMed ID: 8530001) as well as in the compound heterozygous state in patients with congenital bilateral absence of vas deferens (Jezequel et al. 1995. PubMed ID: 7539342; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies suggest that this variant results in a defect of normal CFTR processing (Van Goor et al. 2013. PubMed ID: 23891399; Sosnay et al. 2013. PubMed ID: 23974870), with at least one study suggesting that the p.Arg1070Trp variant may be a more mildly deleterious allele (Krasnov et al. 2008. PubMed ID: 18951463). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.
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. |
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 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.
Comment:
The CFTR c.3208C>T (p.Arg1070Trp) missense variant is well described in the literature as a mild or intermediate variant and is reported to have varying clinical consequences including pancreatic sufficient cystic fibrosis (CF) and congenital bilateral absence of the vas deferens (CBAVD). The p.Arg1070Trp variant has been identified in a compound heterozygous state in at least four studies in six individuals with CBAVD (Jezequel et al. 1995; Mickle et al. 2000; Jezequel et al. 2000; Steiner et al. 2011). The variant has also been reported as part of a complex allele in a compound heterozygous state with a pathogenic splice site variant in a proband with CF (de Prada Merino et al. 2010). Functional studies by Van Goor et al. (2014) demonstrated the p.Arg1070Trp variant resulted in 8% of wild type levels of chloride ion transport. The p.Arg1070Trp variant is reported in the CFTR2 mutation database in a total of 13 alleles (Sosnay et al. 2013), and is described as a "mutation of varying clinical consequence." Incomplete penetrance is documented in association with the p.Arg1070Trp variant; not all individuals who carry this variant along with a second disease-causing CFTR variant in trans will display symptoms of a CFTR-related disorder (CFTR2 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg1070Trp variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The p.Arg1070Trp variant in CFTR has been reported in >20 compound heterozygous individuals (the majority carrying p.Phe508del) primarily affected by milder for ms of CFTR-related disorders (congenital bilateral absence of the vas deferens a nd cystic fibrosis) and more than half of these individuals were reported to hav e normal to low sweat chloride levels (Jezequel 1995, Feldmann 2003, Krasnov 200 8, Pelletier 2010, de Prada Merino 2010, Steiner 2011, Sosnay 2013). In addition , this variant has been identified in 4/66100 of European chromosomes and 1/1034 0 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs202179988). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. In vitro functional studies provide some evidence that the p.Arg1070Trp variant may impact protein function (Krasnov 2008, Sosnay 2013, Van Goor 2014). However, these types of assays may not accurately represent biologi cal function. In summary, this variant meets our criteria to be classified as pa thogenic for CTFR-related disorders including CBAVD and cystic fibrosis in an au tosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) base d upon multiple co-occurrences with pathogenic variants and its low frequency in the general population.
Comment:
The p.R1070W pathogenic mutation (also known as c.3208C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3208. The arginine at codon 1070 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this mutation was identified in conjunction with a second CFTR alteration in 24 individuals with pancreatic sufficient cystic fibrosis or congenital bilateral absence of the vas deferens (CBAVD) (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72). In vitro functional studies showed that cells with this mutation have significantly decreased chloride conductance compared to wild type (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36) and CFTR protein with this mutation was able to process into mature protein but with decreased efficiency compared to wild-type (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72). The p.R1070W alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
In the published literature, the variant has been reported in several individuals affected with CBAVD or non-classic CF (PMID: 18951463 (2008), 20880762 (2010), 21520337 (2011), 26708955 (2016)). In addition, in vitro functional studies show this variant has a deleterious effect on CFTR protein processing, localization, and function (PMID: 18951463 (2008), 23974870 (2013), 23891399 (2014)). However, it was observed to have high chloride channel function in an earlier study (PMID: 10762539 (2000)). Based on the available information, this variant is classified as pathogenic.
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Comment:
Variant summary: CFTR c.3208C>T (p.Arg1070Trp) 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 4.8e-05 in 250962 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3208C>T has been reported in the literature in compound heterozygosity with another pathogenic variant in multiple individuals affected with CFTR-Related Diseases, primarily CBAVD (e.g. Jezequel_1995, Steiner_2011) and Non-Classic Cystic Fibrosis (e.g. McGinnis_2005, Sosnay_2013). These data indicate that the variant is likely to be associated with disease. A worldwide survey of patients with the p.Arg1070Trp variant identified 24 patients with complete clinical data (21 of which had the common pathogenic variant p.Phe508del or another severe CFTR mutation), and included 15 patients with CBAVD, 9 with non-classic CF, and 1 with classic CF phenotypes (Krasnov_2008). A second large survey that collected data from CF registries and clinics in the US and Europe reported the variant in a total of 13 CF alleles, but indicated that only 20% of the individuals were pancreatic-insufficient, with a mean lung function of 93.7%. 16.7% of these patients had tested positive for Pseudomonas (Sosnay_2013). Collectively, the clinical data on patients with this variant suggests that c.3208C>T is most likely a relatively mild mutation that is most often associated with either pancreatic-sufficient non-classic CF or CBAVD when present in trans with a more severe CFTR mutation. Several functional studies evaluating an impact on protein function have reported conflicting conclusions regarding the effects of this variant. One study reported that chloride channel function in cells expressing the variant was comparable to wild-type (e.g. Mickle_2000), however, it has also been reported that chloride conductance in cells expressing the variant was <10% that of wild-type (e.g. Van Goor_2013, Sosnay_2013). CFTR maturation and the amount of protein expression was 91% and 67.8% of the wild-type as measured in HeLa cells and FRT cells, respectively (Sosnay_2013), and the variant was reported to retain localization to the apical membrane, albeit less efficiently than the wild-type protein (e.g. Krasnov_2008). Eleven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified teh variant VUS (n=1), likely pathogenic (n=1) and pathogenic (n=9). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies demonstrate a damaging effect: reduced cell surface expression and chloride transport with defective channel gating (Seibert et al., 1996; Sosnay et al., 2013; VanGoor et al., 2014); Observed with a pathogenic variant in patients with cystic fibrosis or CFTR-related disorders (Jezequel et al., 2000; McGinniss et al., 2005; Krasnov et al., 2008; Lebecque et al., 2011; Baldwin et al., 2019); 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: 8530001, 31036917, 27171515, 30873022, 25087612, 21520337, 23891399, 20460946, 21228398, 27469177, 8662892, 18951463, 10762539, 23974870, 7539342, 26708955, 20837875, 17331079, 11101688, 26014425, 16189704, 12955726, 12815607, 20880762, 35327663, 31268981, 34996830, 33374015, 35451201)
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1070 of the CFTR protein (p.Arg1070Trp). This variant is present in population databases (rs202179988, gnomAD 0.01%). This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferens (PMID: 7539342, 10923036, 12167682, 15070876). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53685). 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: 18951463, 23891399). For these reasons, this variant has been classified as Pathogenic.
Comment:
The CFTR c.3208C>T; p.Arg1070Trp variant (rs202179988) is reported in the literature in dozens of individuals affected with cystic fibrosis (CF) or other CFTR-related disorders (Jezequel 1995, Krasnov 2008, Sosnay 2013, CFTR2 database). Most patients carrying p.Arg1070Trp and a second CF-causing variant exhibit non-classic CF or milder symptoms such as congenital absence of the vas deferens or pancreatitis, although a minority of patients are reported with pancreatic-insufficient CF (Krasnov 2008, CFTR2 database). Functional studies suggest p.Arg1070 affects CFTR function and reduces chloride transport activity (Van Goor 2014). This variant is reported as likely pathogenic or pathogenic in ClinVar (Variation ID: 53685), and it is found in the general population with an overall frequency of 0.005% (14/282342 alleles) in the Genome Aggregation Database. Additionally, other amino acid substitutions at this codon (p.Arg1070Gln, p.Arg1070Pro) have been reported in individuals with CF or CFTR-related disorders and are considered disease-causing (Krasnov 2008, Sosnay 2013, CFTR2 database). Based on available information, the p.Arg1070Trp variant is considered to be pathogenic with varying clinical consequences. References: CFTR2 database: http://cftr2.org/ 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. Krasnov KV et al. Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships. Hum Mutat. 2008 Nov;29(11):1364-72. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. 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.
Comment:
This sequence change is predicted to replace arginine with tryptophan at codon 1070 of the CFTR protein, p.(Arg1070Trp). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the fourth cytoplasmic loop of the cystic fibrosis transmembrane (CL4). There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.005%, which is consistent with recessive disease (rs202179988, 14/282,342 alleles, 0 homozygotes in gnomAD v2.1). It is classified as a CFTR variant of varying clinical consequences, and has been identified with a second pathogenic allele (mainly p.Phe508del) in non-classic pancreatic cystic fibrosis (CF), congenital bilateral absence of the vas deferens, and recurrent pancreatitis (for example PMID: 18951463, 31268981). The variant has also been identified as part of a complex allele that causes classic CF, when found in trans with a second pathogenic variant (PMID: 20880762). In vitro functional assays demonstrate that the variant causes mild defects on chloride transport and is inserted into the apical membrane at reduced levels (PMID: 8662892, 18951463, 23891399). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Additionally, there is a different missense change (p.Arg1070Gln) at the same position determined to be pathogenic (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM5, PS3_Supporting, PM2_Supporting, PP3.
Comment:
The CFTR c.3208C>T variant is predicted to result in the amino acid substitution p.Arg1070Trp. This variant has been reported in cohorts of individuals with suspected cystic fibrosis (see, for example, Krasnov et al. 2008. PubMed ID: 18951463; Pelletier et al. 2010. PubMed ID: 20460946; Ferec et al. 1995. PubMed ID: 8530001) as well as in the compound heterozygous state in patients with congenital bilateral absence of vas deferens (Jezequel et al. 1995. PubMed ID: 7539342; Steiner et al. 2011. PubMed ID: 21520337). In vitro studies suggest that this variant results in a defect of normal CFTR processing (Van Goor et al. 2013. PubMed ID: 23891399; Sosnay et al. 2013. PubMed ID: 23974870), with at least one study suggesting that the p.Arg1070Trp variant may be a more mildly deleterious allele (Krasnov et al. 2008. PubMed ID: 18951463). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Andrological findings in infertile men with two (biallelic) CFTR mutations: results of a multicentre study in Germany and Austria comprising 71 patients. | Rudnik-Schöneborn S | Human reproduction (Oxford, England) | 2021 | PMID: 33374015 |
| Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity. | Prins S | The Journal of biological chemistry | 2020 | PMID: 32934006 |
| Full Rescue of F508del-CFTR Processing and Function by CFTR Modulators Can Be Achieved by Removal of Two Regulatory Regions. | Uliyakina I | International journal of molecular sciences | 2020 | PMID: 32630527 |
| Characterization of the mechanism of action of RDR01752, a novel corrector of F508del-CFTR. | Lopes-Pacheco M | Biochemical pharmacology | 2020 | PMID: 32628927 |
| Should isolated Pseudo-Bartter syndrome be considered a CFTR-related disorder of infancy? | Poli P | Pediatric pulmonology | 2019 | PMID: 31328366 |
| Acute Recurrent and Chronic Pancreatitis as Initial Manifestations of Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders. | Baldwin C | Pancreas | 2019 | PMID: 31268981 |
| Sequencing as a first-line methodology for cystic fibrosis carrier screening. | Beauchamp KA | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31036917 |
| Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine. | Pranke I | Frontiers in pharmacology | 2019 | PMID: 30873022 |
| Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators. | Laselva O | Frontiers in pharmacology | 2018 | PMID: 30022950 |
| Partial rescue of F508del-cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual-acting small molecule. | Liu J | British journal of pharmacology | 2018 | PMID: 29318594 |
| Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis. | Ideozu JE | International journal of molecular sciences | 2017 | PMID: 28800122 |
| CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. | Claustres M | Human mutation | 2017 | PMID: 28603918 |
| Molecular Genetics of Cystic Fibrosis Transmembrane Conductance Regulator: Genotype and Phenotype. | Sosnay PR | Pediatric clinics of North America | 2016 | PMID: 27469177 |
| Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. | Palermo JJ | Pancreas | 2016 | PMID: 27171515 |
| The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. | Schrijver I | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26708955 |
| The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus. | Girardet A | European journal of human genetics : EJHG | 2016 | PMID: 26014425 |
| Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
| 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 |
| Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
| Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
| ABPA in adulthood: a CFTR-related disorder. | Lebecque P | Thorax | 2011 | PMID: 20837875 |
| [R74W;R1070W;D1270N]: a new complex allele responsible for cystic fibrosis. | de Prada Merino A | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2010 | PMID: 20880762 |
| The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis. | Thibodeau PH | The Journal of biological chemistry | 2010 | PMID: 20667826 |
| CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. | Pelletier AL | Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] | 2010 | PMID: 20460946 |
| Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships. | Krasnov KV | Human mutation | 2008 | PMID: 18951463 |
| Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. | Alonso MJ | Annals of human genetics | 2007 | PMID: 17331079 |
| Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. | McGinniss MJ | Human genetics | 2005 | PMID: 16189704 |
| Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. | Dayangaç D | Human reproduction (Oxford, England) | 2004 | PMID: 15070876 |
| CFTR genotypes in patients with normal or borderline sweat chloride levels. | Feldmann D | Human mutation | 2003 | PMID: 12955726 |
| Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland. | Scotet V | Human mutation | 2003 | PMID: 12815607 |
| Variant cystic fibrosis phenotypes in the absence of CFTR mutations. | Groman JD | The New England journal of medicine | 2002 | PMID: 12167682 |
| 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 |
| Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. | Claustres M | Human mutation | 2000 | PMID: 10923036 |
| Effects of cystic fibrosis and congenital bilateral absence of the vas deferens-associated mutations on cystic fibrosis transmembrane conductance regulator-mediated regulation of separate channels. | Mickle JE | American journal of human genetics | 2000 | PMID: 10762539 |
| 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 |
| Neonatal screening for cystic fibrosis: result of a pilot study using both immunoreactive trypsinogen and cystic fibrosis gene mutation analyses. | Férec C | Human genetics | 1995 | PMID: 8530001 |
| Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. | Jézéquel P | Clinical chemistry | 1995 | PMID: 7539342 |
| https://www.pharmgkb.org/clinicalAnnotation/1449191740 | - | - | - | - |
| https://www.pharmgkb.org/variant/PA166164956 | - | - | - | - |
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Text-mined citations for rs202179988 ...
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Record last updated Nov 25, 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.