VCV000007122.134 - ClinVar

NM_000492.4(CFTR):c.1657C>T (p.Arg553Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

30 submissions

29 submitters

7 conditions

Practice guidelines

Pathogenic

Mar 2004 by American Colle…

for Cystic fibrosis

Reviewed by expert panel

Pathogenic

Mar 2017 by CFTR2

for Cystic fibrosis

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.1657C>T (p.Arg553Ter)

Variation ID: 7122 Accession: VCV000007122.134

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117587811 (GRCh38) [ NCBI UCSC ] 7: 117227865 (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	Mar 24, 2015	Dec 22, 2024	Mar 3, 2004

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1657C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Arg553Ter	nonsense
NC_000007.14:g.117587811C>T
NC_000007.13:g.117227865C>T
NG_016465.4:g.127028C>T
NG_056131.3:g.766C>T
LRG_663:g.127028C>T
LRG_663t1:c.1657C>T	LRG_663p1:p.Arg553Ter

... more HGVS ... less HGVS

Protein change

R553*

Other names

Canonical SPDI

NC_000007.14:117587810: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), exomes 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00010

Exome Aggregation Consortium (ExAC) 0.00012

The Genome Aggregation Database (gnomAD) 0.00012

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

Genetic Testing Registry (GTR): GTR000556535 Genetic Testing Registry (GTR): GTR000576392 OMIM: 602421.0014 dbSNP: rs74597325 ClinGen: CA340635 Genetic Testing Registry (GTR): GTR000074114 Genetic Testing Registry (GTR): GTR000257096 Genetic Testing Registry (GTR): GTR000500233 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	3844	5226
LOC111674475	-	-	-	GRCh38	-	146

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.
Cystic fibrosis	Pathogenic (15)	practice guideline	Mar 3, 2004	RCV000007542.46
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Oct 23, 2023	RCV000506601.33
not specified	Pathogenic (1)	criteria provided, single submitter	Oct 6, 2017	RCV000781237.11
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Apr 13, 2022	RCV000763575.11
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	-	RCV001004260.9
CFTR-related disorder	Pathogenic (2)	criteria provided, single submitter	Oct 3, 2023	RCV001831525.10
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV003137499.10

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.
pathogenic (Mar 03, 2004)	practice guideline (Guideline for cystic fibrosis carrier screening) Method: curation	Cystic fibrosis (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	American College of Medical Genetics and Genomics (ACMG) Study: The ACMG recommended carrier screening panel Accession: SCV000071396.2 First in ClinVar: Jun 04, 2013 Last updated: Mar 24, 2015	Publications: PubMed (1) PubMed: 11280952 pmc: 3110945 pmc: 3110945 Comment: Converted during submission to Pathogenic.
Pathogenic (Mar 17, 2017)	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013)) Method: research	Cystic fibrosis Affected status: yes Allele origin: germline	CFTR2 Study: CFTR2 Accession: SCV000071552.4 First in ClinVar: Oct 18, 2013 Last updated: Dec 06, 2016	Other databases https://cftr2.org https://cftr2.org
Pathogenic (Oct 20, 2017)	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: SCV000915204.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (11) PubMed: 21783433‚ 17475917‚ 21097845‚ 25580864‚ 1695717‚ 1518030‚ 1682496‚ 2233965‚ 7693946‚ 15482777‚ 16283068 Comment: The CFTR c.1657C>T (p.Arg553Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg553Ter variant has been reported in … (more) The CFTR c.1657C>T (p.Arg553Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg553Ter variant has been reported in at least 11 studies in which it is found in a total of 17 individuals with CFTR-related disorders including in three individuals in a homozygous state, in 12 individuals in a compound heterozygous state (of which at least three are related) and in one affected individual in heterozygous state. The severity of the disease varied among these individuals from very mild to severe with a range of phenotypes including classic cystic fibrosis, pancreatic insufficiency, pulmonary disease and male infertility due to congenital bilateral absence of vas deferens without pulmonary or gastrointestinal symptoms. This variant has also been reported in a heterozygous state in six unaffected relatives of affected individuals (Cutting et al. 1990a; Cutting et al 1990b; Bal et al. 1991; Cheadle et al. 1992; Will et al. 1993; Wong et al. 2004; Chen et al. 2005; Aznarez et al. 2007; Sheridan et al. 2011; Costa et al. 2011; Liu et al. 2015). The p.Arg553Ter variant was shown to result in no detectable CFTR mRNA in nasal epithelial cells and lymphocytes derived from a severely affected individual who carried the variant in a compound heterozygous state (Will et al. 1993). RT-PCR studies in patient lymphoblastoid cells lines demonstrated that the p.Arg553Ter variant results in the skipping of exon 11 through the creation of a putative exonic splicing silencer (Aznarez et al. 2007). Control data are unavailable for the p.Arg553Ter variant which is reported at a frequency of 0.000581 in the European American population of the Exome Sequencing Project. Based on the evidence and the potential impact of stop-gained variants, the pArg553Ter 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 (Oct 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CFTR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004108246.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The CFTR c.1657C>T variant is predicted to result in premature protein termination (p.Arg553). This variant is documented causative for cystic fibrosis (see, for example, Cutting … (more) The CFTR c.1657C>T variant is predicted to result in premature protein termination (p.Arg553). This variant is documented causative for cystic fibrosis (see, for example, Cutting et al. 1990. PubMed ID: 1695717). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117227865-C-T). Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Oct 23, 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: SCV000883602.5 First in ClinVar: Dec 15, 2018 Last updated: Feb 20, 2024	Comment: The CFTR c.1657C>T; p.Arg553Ter variant (rs74597325) is reported in multiple cystic fibrosis patients with pancreatic insufficiency (Bal 1991, Cheadle 1992, Chen 2005, Cutting 1990, Cutting … (more) The CFTR c.1657C>T; p.Arg553Ter variant (rs74597325) is reported in multiple cystic fibrosis patients with pancreatic insufficiency (Bal 1991, Cheadle 1992, Chen 2005, Cutting 1990, Cutting 1990b, Gallati 2009, Ooi 2012, Sheridan 2011, Sosnay 2013, CFTR2 database). Functional characterization indicates that the variant not only leads to severe mRNA depletion (Hamosh 1992), but also causes aberrant splicing (skipping of exon 11) that results in a frameshift (Aznarez 2007). This variant is reported in ClinVar (Variation ID: 7122). It is observed in the general population with an overall allele frequency of 0.007% (20/282170 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org Aznarez I et al. Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X. J Med Genet. 2007 May;44(5):341-6. Bal J et al. A cystic fibrosis patient homozygous for the nonsense mutation R553X. J Med Genet. 1991 Oct;28(10):715-7. Cheadle J et al. Mild pulmonary disease in a cystic fibrosis child homozygous for R553X. J Med Genet. 1992 Aug;29(8):597. Chen HJ et al. Cystic fibrosis with homozygous R553X mutation in a Taiwanese child. J Hum Genet. 2005;50(12):674-8. Cutting GR et al. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990 Jul 26;346(6282):366-9. Cutting GR et al. Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease. N Engl J Med. 1990b Dec 13;323(24):1685-9. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. Hamosh A et al. CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Hum Mol Genet. 1992 Oct;1(7):542-4. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Sheridan MB et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011 Apr;48(4):235-41. 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. (less)
Pathogenic (Jan 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713428.2 First in ClinVar: Jun 15, 2021 Last updated: Jun 09, 2024	Other databases https://cftr2.org/ https://cftr2.org/ Number of individuals with the variant: 4
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197458.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Aug 15, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331128.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR Number of individuals with the variant: 5 Zygosity: Homozygote, Single Heterozygote Sex: mixed
Pathogenic (Mar 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cystic fibrosis (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Center for Precision Medicine, Vanderbilt University Medical Center Accession: SCV000889998.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018	Publications: PubMed (1) PubMed: 29590070 Number of individuals with the variant: 12 Clinical Features: chronic airway obstruction (present) , acute upper respiratory infections (present) , pneumonia (present) , hypovolemia (present) , bronchiectasis (present) , diseases of the pancreas (present) … (more) chronic airway obstruction (present) , acute upper respiratory infections (present) , pneumonia (present) , hypovolemia (present) , bronchiectasis (present) , diseases of the pancreas (present) , asthma (present) , intestinal malabsorption (present) , idiopathic fibrosing alveolitis (present) , acute bronchitis and bronchiolitis (present) , anal and rectal conditions (present) (less) Zygosity: Single Heterozygote Method: A phenotype risk score (PheRS) for Cystic fibrosis was calculated by mapping the disease HPO terms to phecodes, clustered ICD-9 codes that represent phenotypes in the electronic health records. When applied to 21,701 European individuals, the PheRS for this disease showed significant association with the rs74597325 variant. Some individuals that are heterozygous for this variant carry phecodes that are consistent with phenotypes associated with this disease. 3/12 of the individuals carrying this variant (all heterozygotes) were diagnosed with Cystic fibrosis.
Pathogenic (Oct 06, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000919142.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (5) PubMed: 15480987‚ 1721624‚ 12767731‚ 23974870‚ 15371902 Comment: Variant summary: The CFTR c.1657C>T (p.Arg553X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense … (more) Variant summary: The CFTR c.1657C>T (p.Arg553X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.1742dupT [p.Leu581fsX8] and c.1792_1798delAAAACTA [p.Lys598fsX11]). One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/276546 control chromosomes at a frequency of 0.0000759, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant is a well-characterized, disease-causing mutation in CFTR - in a study of 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe, the variant was present in 645 CF patients; and of the 369 patients included in the analsyis, 96.1% were pancreatic insufficient (Sosnay_2013). RNA from nasal epithelial cells of a patient with the genotype S549N/R553X showed that <2% of the transcripts were derived from R553X (Hamosh_1991). Additionally, chloride secretion in a rectal biopsy specimens from 3 patients with the genotype deltaF508/R553X found that Cl-secretion was 0% of control, suggesting that R553X is non-functional (Hirtz_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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: SCV001163136.1 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 Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169410.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918
Pathogenic (Nov 12, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194074.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (1) PubMed: 23974870 Comment: NM_000492.3(CFTR):c.1657C>T(R553) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include … (more) NM_000492.3(CFTR):c.1657C>T(R553) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1657C>T(R553*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: germline	3billion Accession: SCV002058283.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022	Publications: PMID:1695717 PMID:1695717 Comment: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more) Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000007122, PMID:1695717).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000071, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal sweat electrolytes (present) , Bronchiectasis (present) , Exocrine pancreatic insufficiency (present) , Failure to thrive (present) , Global developmental delay (present) , Hypochloremic metabolic … (more) Abnormal sweat electrolytes (present) , Bronchiectasis (present) , Exocrine pancreatic insufficiency (present) , Failure to thrive (present) , Global developmental delay (present) , Hypochloremic metabolic alkalosis (present) , Recurrent pneumonia (present) (less) Zygosity: Single Heterozygote
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: SCV000886201.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Apr 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894414.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Oct 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bronchiectasis with or without elevated sweat chloride 1 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003806966.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong, PP1 supporting Number of individuals with the variant: 1 Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Oct 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: SCV000601055.4 First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024	Publications: PubMed (33) PubMed: 1695717‚ 22658665‚ 23974870‚ 11924117‚ 15482777‚ 16283068‚ 1682496‚ 1715308‚ 1723032‚ 18456578‚ 19176844‚ 20021716‚ 21097845‚ 21520337‚ 22020151‚ 22975760‚ 25087612‚ 25525159‚ 25869325‚ 29261177‚ 30487145‚ 30842938‚ 31036917‚ 31589614‚ 32429104‚ 32539862‚ 32777524‚ 7545856‚ 7693946‚ 9806422‚ 25580864‚ 28603918‚ 29590070 Comment: This nonsense variant causes the premature termination of CFTR protein synthesis. In the published literature, the variant has been reported in individuals affected with CF … (more) This nonsense variant causes the premature termination of CFTR protein synthesis. In the published literature, the variant has been reported in individuals affected with CF or a CFTR-related disease (PMID: 1695717 (1990), 23974870 (2013), 25580864 (2015), 29590070 (2018)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 18, 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: SCV000074407.11 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 28492532‚ 1695717‚ 7691345‚ 9725922‚ 7693946‚ 9272157‚ 16283068‚ 21520337‚ 22658665‚ 23974870 Comment: This sequence change creates a premature translational stop signal (p.Arg553) in the CFTR gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg553) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs74597325, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis, congenital absence of the vas deferens, and recurrent pancreatitis (PMID: 1695717, 7693946, 9272157, 16283068, 21520337, 22658665, 23974870). 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: 7122). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 29, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002707106.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.R553* pathogenic mutation (also known as c.1657C>T), located in coding exon 12 of the CFTR gene, results from a C to T substitution at … (more) The p.R553* pathogenic mutation (also known as c.1657C>T), located in coding exon 12 of the CFTR gene, results from a C to T substitution at nucleotide position 1657. This changes the amino acid at codon 553 from an arginine to a stop codon. This mutation was first described in two African American individuals with cystic fibrosis, one of whom was compound heterozygous for a pathogenic CFTR mutation on the other chromosome (Cutting GR et al. Nature.1990;346(6282):366-369). One study described a homozygous individual who presented with pancreatic insufficiency (PI) and elevated sweat chloride levels (Stanke F et al. J Med Genet. 2008;45(1):47-54). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Mar 26, 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: SCV004213271.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Aug 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002573980.2 First in ClinVar: Sep 24, 2022 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PM3_VSTR Sex: female
Pathogenic (Dec 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005438159.1 First in ClinVar: Dec 22, 2024 Last updated: Dec 22, 2024
Pathogenic (May 01, 2007)	no assertion criteria provided Method: literature only	CYSTIC FIBROSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027743.6 First in ClinVar: Apr 04, 2013 Last updated: May 14, 2018	Publications: PubMed (6) PubMed: 1695717‚ 1682496‚ 2233965‚ 1518030‚ 16283068‚ 17475917 Hamosh, A. Personal Communication. (more...) Hamosh, A. Personal Communication. 2018. Baltimore, Md. Comment on evidence: In a patient with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a C-to-T change at nucleotide 1789 in exon 11 of the CFTR … (more) In a patient with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a C-to-T change at nucleotide 1789 in exon 11 of the CFTR gene that was responsible for a stop mutation at amino acid 553 (R553X). Bal et al. (1991) described a patient homozygous for the arg553-to-ter mutation in exon 11. The patient was moderately severely affected. Hamosh et al. (1991) studied a CF patient who was a compound heterozygote for 2 nonsense mutations, R553X and W1316X (602421.0029). The patient had undetectable CFTR mRNA in bronchial and nasal epithelial cells associated with severe pancreatic disease but unexpectedly mild pulmonary disease. The R553X mutation has the fourth highest frequency worldwide, 1.5%, according to the CF Consortium (Hamosh et al., 1991). The patient was a 22-year-old African American female, 1 of 2 patients with mild pulmonary disease reported by Cutting et al. (1990). Cheadle et al. (1992) described a child who despite being homozygous for the R553X mutation had only mild pulmonary disease. They raised the possibility that the lack of CFTR protein in airway cells may be less damaging than the presence of an altered protein, a suggestion advanced by Cutting et al. (1990). Chen et al. (2005) reported a Taiwanese CF patient who was homozygous for the R553X mutation. He had a severe clinical course, with early onset of chronic diarrhea, failure to thrive, and frequent respiratory infections. The parents, who were not related, were both heterozygous for the mutation. Both of their families were native to Taiwan, having been on the island for at least 3 generations. Chen et al. (2005) noted that cystic fibrosis is rare among Asians and that homozygosity for R553X had only been reported previously in Caucasian patients. Aznarez et al. (2007) performed transcript analysis of 5 CF patients who were compound heterozygous for the R553X and delta-F508 (602421.0001) mutations. RT-PCR of patient lymphoblastoid cells showed variable levels of an aberrantly spliced CFTR isoform that corresponded to the skipping of exon 11. Use of a splice reporter construct indicated that the R553X substitution creates a putative exonic splicing silencer (ESS) that may result in exon skipping by preventing selection of the proximal 5-prime splice site. Exon 11 skipping did not result from a nonsense-associated altered splicing mechanism. Aznarez et al. (2007) concluded that aminoglycoside treatment would not be effective for CF patients with this mutation owing to its effect of skipping exon 11. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744681.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953098.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972734.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002080638.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
Pathogenic (Dec 25, 2023)	no assertion criteria provided Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: paternal, maternal	Department of Urology, First Affiliated Hospital of Nanjing Medical University Accession: SCV004217831.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Other databases https://cftr2.org https://cftr2.org Observation 1: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: Asian Testing laboratory: MyGenostics Company (Beijing, China) Date variant was reported to submitter: 2017-12-12 Observation 2: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Asian Testing laboratory: Shanghai Institute of Pediatric Research Date variant was reported to submitter: 2021-09-29
not provided (-)	no classification provided Method: literature only	Cystic fibrosis Affected status: unknown Allele origin: unknown	GeneReviews Accession: SCV001622790.2 First in ClinVar: May 23, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301428‚ 15371902 BookShelf: NBK1250 BookShelf: NBK1250
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Comment:

The CFTR c.1657C>T (p.Arg553Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg553Ter variant has been reported in at least 11 studies in which it is found in a total of 17 individuals with CFTR-related disorders including in three individuals in a homozygous state, in 12 individuals in a compound heterozygous state (of which at least three are related) and in one affected individual in heterozygous state. The severity of the disease varied among these individuals from very mild to severe with a range of phenotypes including classic cystic fibrosis, pancreatic insufficiency, pulmonary disease and male infertility due to congenital bilateral absence of vas deferens without pulmonary or gastrointestinal symptoms. This variant has also been reported in a heterozygous state in six unaffected relatives of affected individuals (Cutting et al. 1990a; Cutting et al 1990b; Bal et al. 1991; Cheadle et al. 1992; Will et al. 1993; Wong et al. 2004; Chen et al. 2005; Aznarez et al. 2007; Sheridan et al. 2011; Costa et al. 2011; Liu et al. 2015). The p.Arg553Ter variant was shown to result in no detectable CFTR mRNA in nasal epithelial cells and lymphocytes derived from a severely affected individual who carried the variant in a compound heterozygous state (Will et al. 1993). RT-PCR studies in patient lymphoblastoid cells lines demonstrated that the p.Arg553Ter variant results in the skipping of exon 11 through the creation of a putative exonic splicing silencer (Aznarez et al. 2007). Control data are unavailable for the p.Arg553Ter variant which is reported at a frequency of 0.000581 in the European American population of the Exome Sequencing Project. Based on the evidence and the potential impact of stop-gained variants, the pArg553Ter 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 CFTR c.1657C>T variant is predicted to result in premature protein termination (p.Arg553*). This variant is documented causative for cystic fibrosis (see, for example, Cutting et al. 1990. PubMed ID: 1695717). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117227865-C-T). Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

The CFTR c.1657C>T; p.Arg553Ter variant (rs74597325) is reported in multiple cystic fibrosis patients with pancreatic insufficiency (Bal 1991, Cheadle 1992, Chen 2005, Cutting 1990, Cutting 1990b, Gallati 2009, Ooi 2012, Sheridan 2011, Sosnay 2013, CFTR2 database). Functional characterization indicates that the variant not only leads to severe mRNA depletion (Hamosh 1992), but also causes aberrant splicing (skipping of exon 11) that results in a frameshift (Aznarez 2007). This variant is reported in ClinVar (Variation ID: 7122). It is observed in the general population with an overall allele frequency of 0.007% (20/282170 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org Aznarez I et al. Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X. J Med Genet. 2007 May;44(5):341-6. Bal J et al. A cystic fibrosis patient homozygous for the nonsense mutation R553X. J Med Genet. 1991 Oct;28(10):715-7. Cheadle J et al. Mild pulmonary disease in a cystic fibrosis child homozygous for R553X. J Med Genet. 1992 Aug;29(8):597. Chen HJ et al. Cystic fibrosis with homozygous R553X mutation in a Taiwanese child. J Hum Genet. 2005;50(12):674-8. Cutting GR et al. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990 Jul 26;346(6282):366-9. Cutting GR et al. Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease. N Engl J Med. 1990b Dec 13;323(24):1685-9. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. Hamosh A et al. CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Hum Mol Genet. 1992 Oct;1(7):542-4. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. Sheridan MB et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011 Apr;48(4):235-41. 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.

Comment:

Variant summary: The CFTR c.1657C>T (p.Arg553X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.1742dupT [p.Leu581fsX8] and c.1792_1798delAAAACTA [p.Lys598fsX11]). One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/276546 control chromosomes at a frequency of 0.0000759, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant is a well-characterized, disease-causing mutation in CFTR - in a study of 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe, the variant was present in 645 CF patients; and of the 369 patients included in the analsyis, 96.1% were pancreatic insufficient (Sosnay_2013). RNA from nasal epithelial cells of a patient with the genotype S549N/R553X showed that <2% of the transcripts were derived from R553X (Hamosh_1991). Additionally, chloride secretion in a rectal biopsy specimens from 3 patients with the genotype deltaF508/R553X found that Cl-secretion was 0% of control, suggesting that R553X is non-functional (Hirtz_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

NM_000492.3(CFTR):c.1657C>T(R553*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1657C>T(R553*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000007122, PMID:1695717).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000071, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This nonsense variant causes the premature termination of CFTR protein synthesis. In the published literature, the variant has been reported in individuals affected with CF or a CFTR-related disease (PMID: 1695717 (1990), 23974870 (2013), 25580864 (2015), 29590070 (2018)). Based on the available information, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg553*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs74597325, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis, congenital absence of the vas deferens, and recurrent pancreatitis (PMID: 1695717, 7693946, 9272157, 16283068, 21520337, 22658665, 23974870). 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: 7122). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R553* pathogenic mutation (also known as c.1657C>T), located in coding exon 12 of the CFTR gene, results from a C to T substitution at nucleotide position 1657. This changes the amino acid at codon 553 from an arginine to a stop codon. This mutation was first described in two African American individuals with cystic fibrosis, one of whom was compound heterozygous for a pathogenic CFTR mutation on the other chromosome (Cutting GR et al. Nature.1990;346(6282):366-369). One study described a homozygous individual who presented with pancreatic insufficiency (PI) and elevated sweat chloride levels (Stanke F et al. J Med Genet. 2008;45(1):47-54). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients.	Luo S	Gene	2021	PMID: 32777524
Characterization of clinical and genetic spectrum of Chinese patients with cystic fibrosis.	Liu K	Orphanet journal of rare diseases	2020	PMID: 32539862
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.	Petrova NV	Genes	2020	PMID: 32429104
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
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
Liver Failure in a Chinese Cystic Fibrosis Child With Homozygous R553X Mutation.	Li H	Frontiers in pediatrics	2019	PMID: 30842938
High-frequency actionable pathogenic exome variants in an average-risk cohort.	Rego S	Cold Spring Harbor molecular case studies	2018	PMID: 30487145
Phenotype risk scores identify patients with unrecognized Mendelian disease patterns.	Bastarache L	Science (New York, N.Y.)	2018	PMID: 29590070
Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests.	Archibald AD	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29261177
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
Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment.	Chang MC	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2015	PMID: 25869325
Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients.	Liu Y	Respirology (Carlton, Vic.)	2015	PMID: 25580864
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
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
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.	Lazarin GA	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22975760
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis.	Ooi CY	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2012	PMID: 22658665
Extensive molecular analysis of patients bearing CFTR-related disorders.	Amato F	The Journal of molecular diagnostics : JMD	2012	PMID: 22020151
A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice.	Costa C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2011	PMID: 21783433
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.	Steiner B	Human mutation	2011	PMID: 21520337
CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR.	Sheridan MB	Journal of medical genetics	2011	PMID: 21097845
CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening.	Chávez-Saldaña M	Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion	2010	PMID: 21416780
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners.	Gallati S	Reproductive biomedicine online	2009	PMID: 20021716
Transient correction of the basic defect in sweat glands in an individual with cystic fibrosis carrying the complex CFTR allele F508del-R553Q.	Tümmler B	Thorax	2009	PMID: 19176844
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.	Castellani C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18456578
Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X.	Aznarez I	Journal of medical genetics	2007	PMID: 17475917
Cystic fibrosis with homozygous R553X mutation in a Taiwanese child.	Chen HJ	Journal of human genetics	2005	PMID: 16283068
Chloride transport in nasal ciliated cells of cystic fibrosis heterozygotes.	Sermet-Gaudelus I	American journal of respiratory and critical care medicine	2005	PMID: 15709055
The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization.	Wong LJ	Fertility and sterility	2004	PMID: 15482777
CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.	Hirtz S	Gastroenterology	2004	PMID: 15480987
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.	Watson MS	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15371902
Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study.	McKone EF	Lancet (London, England)	2003	PMID: 12767731
Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia.	Banjar H	Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit	1999	PMID: 11924117
The association of nonsense codons with exon skipping.	Valentine CR	Mutation research	1998	PMID: 9806422
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.	Cohn JA	The New England journal of medicine	1998	PMID: 9725922
Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens.	Dörk T	Human genetics	1997	PMID: 9272157
Molecular and clinical findings in Austrian cystic fibrosis patients with mutations in exon 11 of the CFTR gene.	Greil I	Wiener klinische Wochenschrift	1995	PMID: 7545856
CFTR transcripts are undetectable in lymphocytes and respiratory epithelial cells of a CF patient homozygous for the nonsense mutation R553X.	Will K	Journal of medical genetics	1993	PMID: 7693946
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.	Yang Y	Human molecular genetics	1993	PMID: 7691345
Mild pulmonary disease in a cystic fibrosis child homozygous for R553X.	Cheadle J	Journal of medical genetics	1992	PMID: 1518030
Nine mutations in the cystic fibrosis (CF) gene account for 80% of the CF chromosomes in French patients.	Simon-Bouy B	Clinical genetics	1991	PMID: 1723032
Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis.	Hamosh A	The Journal of clinical investigation	1991	PMID: 1721624
Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene.	Dörk T	Human genetics	1991	PMID: 1715308
A cystic fibrosis patient homozygous for the nonsense mutation R553X.	Bal J	Journal of medical genetics	1991	PMID: 1682496
Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease.	Cutting GR	The New England journal of medicine	1990	PMID: 2233965
A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.	Cutting GR	Nature	1990	PMID: 1695717
Hamosh, A. Personal Communication. 2018. Baltimore, Md.	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
https://cftr2.org	-	-	-	-
https://cftr2.org/	-	-	-	-
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Text-mined citations for rs74597325 ...

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 Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.1657C>T (p.Arg553Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs74597325 ...