VCV000053947.39 - ClinVar

NM_000492.4(CFTR):c.4426C>T (p.Gln1476Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(18)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.4426C>T (p.Gln1476Ter)

Variation ID: 53947 Accession: VCV000053947.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117667091 (GRCh38) [ NCBI UCSC ] 7: 117307145 (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	Dec 6, 2016	Oct 20, 2024	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.4426C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Gln1476Ter	nonsense
NC_000007.14:g.117667091C>T
NC_000007.13:g.117307145C>T
NG_016465.4:g.206308C>T
NG_056133.2:g.1497C>T
LRG_663:g.206308C>T
LRG_663t1:c.4426C>T	LRG_663p1:p.Gln1476Ter

... more HGVS ... less HGVS

Protein change

Q1476*

Other names

Q1476X

Canonical SPDI

NC_000007.14:117667090: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.

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

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA221031 dbSNP: rs374705585 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	3825	5200
LOC111674477	-	-	-	GRCh38	-	179

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/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Nov 25, 2023	RCV000047135.17
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV000388068.16
not specified	Pathogenic (1)	criteria provided, single submitter	Nov 8, 2016	RCV000505964.8
CFTR-related disorder	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2018	RCV001009479.1
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Likely pathogenic (1)	criteria provided, single submitter	-	RCV001004311.1
Hereditary pancreatitis	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV002247439.3
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	Mar 19, 2022	RCV002477161.1
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Feb 6, 2022	RCV003466915.1

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 (Nov 08, 2016)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602994.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Pathogenic (May 08, 2017)	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: SCV000697026.1 First in ClinVar: Dec 12, 2017 Last updated: Dec 12, 2017	Publications: PubMed (12) PubMed: 17003641‚ 21679131‚ 17449517‚ 12919146‚ 22020151‚ 21520337‚ 11504857‚ 25910067‚ 16784904‚ 15758663‚ 23276700‚ 11938439 Comment: Variant summary: The CFTR c.4426C>T (p.Gln1476X) variant results in a termination codon in the penultimate exon deleting the last four amino acids (Asp-Thr-Arg-Leu). No pathogenic/likely … (more) Variant summary: The CFTR c.4426C>T (p.Gln1476X) variant results in a termination codon in the penultimate exon deleting the last four amino acids (Asp-Thr-Arg-Leu). No pathogenic/likely pathogenic truncating variants downstream of this position have been reported in literature, ClinVar and our laboratory and it is outside of some of the commonly known domains (transmembrane domain, ATPase domain and regulator domain) (InterPro). There are no functional studies for this variant as well. Mutation taster predicts a damaging outcome for this variant. This variant was found in 3/120070 control chromosomes including ExAC at a frequency of 0.000025, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In literature, this variant was found in at least 5 CF patients, 5 CBAVD patients, 3 ICP patients and 3 patients reported to be diagnosed of CFTR-RD. Most patients were known to be compound heterozygotes with another pathogenic variant, primarily with p.Phe508del. In addition, two reported CBAVD patients were found to have elevated sweat chloride implying the diagnosis of CF/NC. Although a nonsense variant, severity of disease associated with this variant is widely reported as mild in literature which can be implicated to its location and resuting functional consequence. One clinical laboratory in ClinVar has classified it as pathogenic. Because CF/NC phenotype has been reported with this variant, and because CBAVD and ICP can also be categorized as manifestation of CF, this variant has been classified as pathogenic with respect to CF/NC phenotype. (less)
Pathogenic (Aug 30, 2013)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331003.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	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: 2 Sex: mixed
Likely 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: SCV001163188.1 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	CFTR-related disorders Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169574.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918
Pathogenic (May 10, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529734.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The CFTR c.4426C>T (p.Q1476X) variant has been reported in compound heterozygocity with another pathogenic variant in individuals with pancreatitis, cystic fibrosis, congenital bilateral absence of … (more) The CFTR c.4426C>T (p.Q1476X) variant has been reported in compound heterozygocity with another pathogenic variant in individuals with pancreatitis, cystic fibrosis, congenital bilateral absence of the vas deferens, or secretory azoospermia (PMID: 21520337, 17003641, 12578973, 21679131, 11938439, 28544683, 23276700, 11504857, 17449517). This nonsense variant creates a premature stop codon at residue 1476 of the CFTR protein, resulting in a truncation of last for amino acid residues (Asp-Thr-Arg-Leu). There are no functional studies describng the effect of this variant on protein function. This variant was observed in 6/282280 chromosomes in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 53947). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (9) PubMed: 21520337‚ 17003641‚ 12578973‚ 21679131‚ 11938439‚ 28544683‚ 23276700‚ 11504857‚ 17449517
Likely pathogenic (May 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002756476.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022	Comment: Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost within the PDZ interaction domain (Moyer et al., 1999), … (more) Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost within the PDZ interaction domain (Moyer et al., 1999), although loss-of-function variants have not been reported downstream of this position in the protein; Published functional studies demonstrate normal protein expression and modulator response, but reduced chloride channel function (Sharma et al., 2018); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31589614, 34426522, 30444886, 11938439, 12919146, 10562297, 17449517, 28603918, 21520337, 23276700, 25910067, 22020151, 25087612, 28544683, 21679131, 16784904, 17003641, 12578973, 11504857, 15758663) (less)
Pathogenic (Mar 19, 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: SCV002779186.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Feb 06, 2022)	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: SCV004215790.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Nov 25, 2023)	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: SCV001582233.4 First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 11938439‚ 22020151‚ 25910067‚ 28544683‚ 30444886 Comment: This sequence change creates a premature translational stop signal (p.Gln1476) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Gln1476) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the CFTR protein. This variant is present in population databases (rs374705585, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 11938439, 22020151, 25910067, 28544683). ClinVar contains an entry for this variant (Variation ID: 53947). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CFTR function (PMID: 30444886). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (May 31, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002628136.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 11938439‚ 12919146‚ 15040442‚ 22020151‚ 28544683‚ 31508243 Comment: The p.Q1476* variant (also known as c.4426C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide … (more) The p.Q1476* variant (also known as c.4426C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4426. This changes the amino acid from a glutamine to a stop codon within coding exon 27. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of CFTR, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 5 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. However, this variant has been reported in the literature in several individuals who are compound heterozygous for p.Q1476* and p.F508del: one individual with idiopathic pancreatitis was subsequently found to have elevated sweat chloride levels (Audrézet MP et al. Eur. J. Hum. Genet., 2002 Feb;10:100-6), two males had elevated sweat chloride levels, congenital bilateral absence of the vas deferens (CBAVD), pancreatic sufficiency, and normal respiratory function (Bienvenu T et al. Clin. Genet., 2003 Sep;64:266-8), a third male was reported to have CBAVD only (Amato F et al. J Mol Diagn, 2012 Jan;14:81-9), another individual had moderate pulmonary symptoms with nasal polyposis and digital clubbing (Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206), and the last individual had a history of bronchiectasis and pseudomonas infection (Sugunaraj JP et al. NPJ Genom Med, 2019 Sep;4:21). This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 4, 2019). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Likely pathogenic (May 27, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CYSTIC FIBROSIS Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001984855.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Comment: This variant affects the last exon of CFTR and is predicted to escape nonsense mediated decay (NMD). The c.4426C>T alteration has been previously reported as … (more) This variant affects the last exon of CFTR and is predicted to escape nonsense mediated decay (NMD). The c.4426C>T alteration has been previously reported as a compound heterozygous change in multiple patients with variable clinical presentation ranging from cystic fibrosis to congenital absence of vas deference, and other CFTR-related disorders such as chronic pancreatitis (PMID: 21520337, 22020151, 23276700, https://cftr2.org/mutation/general/all_cf/Q1476X). In-vitro studies showed that this variant leads to the expression of a mature truncated form of CFTR that moderately affects the channel functioning and is responsive to treatment with lumacaftor, or a combination of both lumacaftor and tezacaftor (PMID: 30444886). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/282280) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.4426C>T (p.Gln1476Ter) variant on protein function. Based on the available evidence, the c.4426C>T (p.Gln1476Ter) variant is classified as Likely Pathogenic. (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518693.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Likely pathogenic (Sep 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cystic fibrosis Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002573879.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project … (more) This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_MOD, PS3_SUP, PM2_SUP, PM3_STR, PP4 (less) Number of individuals with the variant: 1
Pathogenic (Oct 21, 2022)	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: SCV004221701.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (18) PubMed: 32906206‚ 30444886‚ 31589614‚ 34996830‚ 21520337‚ 17449517‚ 17003641‚ 15758663‚ 12919146‚ 12578973‚ 11938439‚ 11504857‚ 28544683‚ 28603918‚ 25910067‚ 23276700‚ 22020151‚ 21679131 Comment: This nonsense variant causes the premature termination of CFTR protein synthesis. The frequency of this variant in the general population, 0.000039 (5/128820 chromosomes, http://gnomad.broadinstitute.org), is … (more) This nonsense variant causes the premature termination of CFTR protein synthesis. The frequency of this variant in the general population, 0.000039 (5/128820 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMIDs: 28544683 (2017), 23276700 (2013), 12919146 (2003), 11938439 (2002)) and cystic fibrosis related disease (CFRD) (PMIDs: 25910067 (2015), 22020151 (2012), 21679131 (2011), 21520337 (2011), 17449517 (2007), 17003641 (2006), 12919146 (2003)). This variant is often detected in trans with another pathogenic CFTR variant in affected individuals (PMIDs: 28544683 (2017), 25910067 (2015), 22020151 (2012)). Functional studies have demonstrated this variant may mildly impact protein function, but additional studies are needed to determine the global impact of this variant on the CFTR gene or gene products (PMID: 30444886 (2018)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004811459.7 First in ClinVar: Apr 15, 2024 Last updated: Oct 20, 2024	Comment: CFTR: PM3:Very Strong, PM2, PVS1:Moderate Number of individuals with the variant: 1
Uncertain significance (Dec 19, 2018)	no assertion criteria provided Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV001132152.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019	Publications: PubMed (5) PubMed: 28544683‚ 16784904‚ 12578973‚ 23276700‚ 11938439
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV002583263.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Publications: PubMed (5) PubMed: 22020151‚ 23276700‚ 30444886‚ 21520337‚ 25087612
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Comment:

Variant summary: The CFTR c.4426C>T (p.Gln1476X) variant results in a termination codon in the penultimate exon deleting the last four amino acids (Asp-Thr-Arg-Leu). No pathogenic/likely pathogenic truncating variants downstream of this position have been reported in literature, ClinVar and our laboratory and it is outside of some of the commonly known domains (transmembrane domain, ATPase domain and regulator domain) (InterPro). There are no functional studies for this variant as well. Mutation taster predicts a damaging outcome for this variant. This variant was found in 3/120070 control chromosomes including ExAC at a frequency of 0.000025, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In literature, this variant was found in at least 5 CF patients, 5 CBAVD patients, 3 ICP patients and 3 patients reported to be diagnosed of CFTR-RD. Most patients were known to be compound heterozygotes with another pathogenic variant, primarily with p.Phe508del. In addition, two reported CBAVD patients were found to have elevated sweat chloride implying the diagnosis of CF/NC. Although a nonsense variant, severity of disease associated with this variant is widely reported as mild in literature which can be implicated to its location and resuting functional consequence. One clinical laboratory in ClinVar has classified it as pathogenic. Because CF/NC phenotype has been reported with this variant, and because CBAVD and ICP can also be categorized as manifestation of CF, this variant has been classified as pathogenic with respect to CF/NC phenotype.

Comment:

Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost within the PDZ interaction domain (Moyer et al., 1999), although loss-of-function variants have not been reported downstream of this position in the protein; Published functional studies demonstrate normal protein expression and modulator response, but reduced chloride channel function (Sharma et al., 2018); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31589614, 34426522, 30444886, 11938439, 12919146, 10562297, 17449517, 28603918, 21520337, 23276700, 25910067, 22020151, 25087612, 28544683, 21679131, 16784904, 17003641, 12578973, 11504857, 15758663)

Comment:

This sequence change creates a premature translational stop signal (p.Gln1476*) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the CFTR protein. This variant is present in population databases (rs374705585, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 11938439, 22020151, 25910067, 28544683). ClinVar contains an entry for this variant (Variation ID: 53947). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CFTR function (PMID: 30444886). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Q1476* variant (also known as c.4426C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4426. This changes the amino acid from a glutamine to a stop codon within coding exon 27. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of CFTR, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 5 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. However, this variant has been reported in the literature in several individuals who are compound heterozygous for p.Q1476* and p.F508del: one individual with idiopathic pancreatitis was subsequently found to have elevated sweat chloride levels (Audrézet MP et al. Eur. J. Hum. Genet., 2002 Feb;10:100-6), two males had elevated sweat chloride levels, congenital bilateral absence of the vas deferens (CBAVD), pancreatic sufficiency, and normal respiratory function (Bienvenu T et al. Clin. Genet., 2003 Sep;64:266-8), a third male was reported to have CBAVD only (Amato F et al. J Mol Diagn, 2012 Jan;14:81-9), another individual had moderate pulmonary symptoms with nasal polyposis and digital clubbing (Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206), and the last individual had a history of bronchiectasis and pseudomonas infection (Sugunaraj JP et al. NPJ Genom Med, 2019 Sep;4:21). This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 4, 2019). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

This variant affects the last exon of CFTR and is predicted to escape nonsense mediated decay (NMD). The c.4426C>T alteration has been previously reported as a compound heterozygous change in multiple patients with variable clinical presentation ranging from cystic fibrosis to congenital absence of vas deference, and other CFTR-related disorders such as chronic pancreatitis (PMID: 21520337, 22020151, 23276700, https://cftr2.org/mutation/general/all_cf/Q1476X). In-vitro studies showed that this variant leads to the expression of a mature truncated form of CFTR that moderately affects the channel functioning and is responsive to treatment with lumacaftor, or a combination of both lumacaftor and tezacaftor (PMID: 30444886). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/282280) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.4426C>T (p.Gln1476Ter) variant on protein function. Based on the available evidence, the c.4426C>T (p.Gln1476Ter) variant is classified as Likely Pathogenic.

Comment:

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_MOD, PS3_SUP, PM2_SUP, PM3_STR, PP4

Comment:

This nonsense variant causes the premature termination of CFTR protein synthesis. The frequency of this variant in the general population, 0.000039 (5/128820 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMIDs: 28544683 (2017), 23276700 (2013), 12919146 (2003), 11938439 (2002)) and cystic fibrosis related disease (CFRD) (PMIDs: 25910067 (2015), 22020151 (2012), 21679131 (2011), 21520337 (2011), 17449517 (2007), 17003641 (2006), 12919146 (2003)). This variant is often detected in trans with another pathogenic CFTR variant in affected individuals (PMIDs: 28544683 (2017), 25910067 (2015), 22020151 (2012)). Functional studies have demonstrated this variant may mildly impact protein function, but additional studies are needed to determine the global impact of this variant on the CFTR gene or gene products (PMID: 30444886 (2018)). Based on the available information, this variant is classified as 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
C FTR variants are associated with chronic bronchitis in smokers.	Saferali A	The European respiratory journal	2022	PMID: 34996830
Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India.	Narang A	Human mutation	2020	PMID: 32906206
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
Predictive value of genomic screening: cross-sectional study of cystic fibrosis in 50,788 electronic health records.	Sugunaraj JP	NPJ genomic medicine	2019	PMID: 31508243
Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis.	Sharma N	PLoS genetics	2018	PMID: 30444886
Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics.	Soltysova A	The clinical respiratory journal	2018	PMID: 28544683
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
A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis.	Lucarelli M	Molecular medicine (Cambridge, Mass.)	2015	PMID: 25910067
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
Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations.	Křenková P	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2013	PMID: 23276700
Extensive molecular analysis of patients bearing CFTR-related disorders.	Amato F	The Journal of molecular diagnostics : JMD	2012	PMID: 22020151
Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment.	Tomaiuolo R	Clinical chemistry and laboratory medicine	2011	PMID: 21679131
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.	Steiner B	Human mutation	2011	PMID: 21520337
Pancreatic phenotype in infants with cystic fibrosis identified by mutation screening.	Cipolli M	Archives of disease in childhood	2007	PMID: 17449517
Highly preferential association of NonF508del CF mutations with the M470 allele.	Ciminelli BM	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2007	PMID: 16784904
Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis.	Keiles S	Pancreas	2006	PMID: 17003641
Reduced CFTR function and the pathobiology of idiopathic pancreatitis.	Cohn JA	Journal of clinical gastroenterology	2005	PMID: 15758663
Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics.	Maquat LE	Nature reviews. Molecular cell biology	2004	PMID: 15040442
Mutations located in exon 24 of the CFTR gene are associated with a mild cystic fibrosis phenotype.	Bienvenu T	Clinical genetics	2003	PMID: 12919146
Effects of C-terminal deletions on cystic fibrosis transmembrane conductance regulator function in cystic fibrosis airway epithelia.	Ostedgaard LS	Proceedings of the National Academy of Sciences of the United States of America	2003	PMID: 12578973
Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis.	Audrézet MP	European journal of human genetics : EJHG	2002	PMID: 11938439
A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models.	Chen JM	Molecular biology and evolution	2001	PMID: 11504857
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
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Text-mined citations for rs374705585 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.4426C>T (p.Gln1476Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs374705585 ...