VCV000053685.41 - ClinVar

NM_000492.4(CFTR):c.3208C>T (p.Arg1070Trp)

Germline

Top reviewed classifications are shown here.

Submission summary:

19 submissions

17 submitters

9 conditions

Reviewed by expert panel

Drug response

Mar 2021 by PharmGKB

for ivacaftor response - Efficacy

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

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

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

R1070W

Other names

Canonical SPDI

NC_000007.14:117611648:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Links

ClinGen: CA327099 UniProtKB: P13569#VAR_011564 dbSNP: rs202179988 VarSome

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
Gene	OMIM	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	3826	5201
LOC111674472	-	-	-	GRCh38	-	400

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.
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 11, 2015	RCV000219441.12
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000507471.17
ivacaftor response - Efficacy	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV000660792.11
Cystic fibrosis	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jan 21, 2024	RCV000757802.25
CFTR-related disorder Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2018	RCV001009384.8
Congenital bilateral absence of vas deferens	Pathogenic (1)	criteria provided, single submitter	Mar 30, 2023	RCV002221194.9
CFTR-related disorder	Pathogenic/Likely pathogenic (2)	no assertion criteria provided	Jun 6, 2024	RCV002228159.12
not specified	Pathogenic (1)	criteria provided, single submitter	Feb 8, 2020	RCV001731338.12
Bronchiectasis with or without elevated sweat chloride 1	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.
drug response Drug-variant association: Efficacy (Mar 24, 2021)	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine) 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	Publications: PubMed (1) PubMed: 23891399 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166164956 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1449191740 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. CYP2C93, HLA-B57:01) 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)
Pathogenic (Nov 02, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) 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	Publications: PubMed (7) PubMed: 23974870‚ 7539342‚ 23891399‚ 10762539‚ 11101688‚ 21520337‚ 20880762 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)
Pathogenic (May 11, 2015)	criteria provided, single submitter (LMM Criteria) 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	Publications: PubMed (10) PubMed: 18951463‚ 23974870‚ 12955726‚ 25087612‚ 21520337‚ 7539342‚ 20880762‚ 21228398‚ 20460946‚ 23891399 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
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) 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
Pathogenic (Jan 29, 2018)	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) 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	Publications: PubMed (1) PubMed: 28603918 Comment: when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Pathogenic (Feb 08, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) 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)
Pathogenic (Dec 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) 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
Pathogenic (Nov 05, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) 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
Pathogenic (Jan 21, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) 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	Publications: PubMed (6) PubMed: 7539342‚ 10923036‚ 12167682‚ 15070876‚ 18951463‚ 23891399 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)
Pathogenic (Oct 22, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) 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	Publications: PubMed (6) PubMed: 10762539‚ 18951463‚ 23891399‚ 23974870‚ 27171515‚ 27469177 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)
Pathogenic (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) 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
pathogenic (Dec 14, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) 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	Publications: PubMed (24) PubMed: 28603918‚ 27171515‚ 26708955‚ 26014425‚ 25087612‚ 28800122‚ 30873022‚ 31328366‚ 32628927‚ 32630527‚ 20667826‚ 30022950‚ 10762539‚ 20880762‚ 31036917‚ 7539342‚ 23891399‚ 21520337‚ 21228398‚ 18951463‚ 20460946‚ 23974870‚ 32934006‚ 29318594 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)
Pathogenic (Jun 20, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) 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	Publications: PubMed (20) PubMed: 12815607‚ 8530001‚ 17331079‚ 12955726‚ 18951463‚ 16189704‚ 20460946‚ 7539342‚ 10762539‚ 20837875‚ 20880762‚ 21520337‚ 23974870‚ 23891399‚ 26014425‚ 27171515‚ 28800122‚ 28603918‚ 30873022‚ 33374015 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)
Likely pathogenic (Dec 05, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) 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)
Pathogenic (Aug 15, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) 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)
Pathogenic (Mar 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital bilateral absence of vas deferens Affected status: yes Allele origin: germline	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	Publications: PubMed (5) PubMed: 8662892‚ 18951463‚ 20880762‚ 23891399‚ 31268981 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)
Pathogenic (Dec 22, 2020)	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002507417.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022
Likely pathogenic (Jun 06, 2024)	no assertion criteria provided Method: clinical testing	CFTR-related condition Affected status: unknown Allele origin: germline	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)
Likely pathogenic (Dec 26, 2018)	no assertion criteria provided Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV001132151.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019	Publications: PubMed (6) PubMed: 23974870‚ 26708955‚ 8662892‚ 10762539‚ 23891399‚ 18951463
click to load more click to collapse

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:

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 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:

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:

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:

Citations for germline classification of this variant

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	-	-	-	-
click to load more click to collapse

Text-mined citations for rs202179988 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.3208C>T (p.Arg1070Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs202179988 ...