VCV000007180.13 - ClinVar

NM_000492.4(CFTR):c.3937C>T (p.Gln1313Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

9 submissions

9 submitters

3 conditions

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.3937C>T (p.Gln1313Ter)

Variation ID: 7180 Accession: VCV000007180.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117652905 (GRCh38) [ NCBI UCSC ] 7: 117292959 (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 29, 2015	May 1, 2024	Mar 17, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.3937C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Gln1313Ter	nonsense
NC_000007.14:g.117652905C>T
NC_000007.13:g.117292959C>T
NG_016465.4:g.192122C>T
LRG_663:g.192122C>T
LRG_663t1:c.3937C>T	LRG_663p1:p.Gln1313Ter

... more HGVS ... less HGVS

Protein change

Q1313*

Other names

Canonical SPDI

NC_000007.14:117652904: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.

Links

ClinGen: CA340650 OMIM: 602421.0076 dbSNP: rs121909026 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

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 (7)	reviewed by expert panel	Mar 17, 2017	RCV000007600.19
CFTR-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 17, 2017	RCV001826441.1
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Apr 12, 2023	RCV003473032.1

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 (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: SCV000071543.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018	Other databases https://cftr2.org https://cftr2.org
Pathogenic (Aug 17, 2020)	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: SCV001432103.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Publications: PubMed (11) PubMed: 17331079‚ 10923036‚ 15858154‚ 20059485‚ 18344710‚ 15698946‚ 7683952‚ 23276700‚ 22658665‚ 23974870‚ 20622033 Comment: Variant summary: CFTR c.3937C>T (p.Gln1313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: CFTR c.3937C>T (p.Gln1313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 250482 control chromosomes. c.3937C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, Audrezet_1993, Alonso_2007, Schrijver_2005, desGeorges_2004, Dorfman_2010, Krenkova_2012). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories and one expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 30, 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: SCV001584845.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 1695717‚ 7691345‚ 9725922‚ 7683952‚ 22658665‚ 23974870 Comment: This sequence change creates a premature translational stop signal (p.Gln1313) 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.Gln1313) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7683952, 22658665, 23974870). This variant is also known as c.4069C>T. ClinVar contains an entry for this variant (Variation ID: 7180). For these reasons, this variant has been classified as Pathogenic. (less)
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: SCV001169365.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918
Pathogenic (Apr 12, 2023)	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: SCV004213529.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Jun 29, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002624320.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 23974870‚ 7683952 Comment: The p.Q1313* pathogenic mutation (also known as c.3937C>T, c.4069C>T and p.Q1313X) is located in coding exon 24 of the CFTR gene. In one study, this … (more) The p.Q1313* pathogenic mutation (also known as c.3937C>T, c.4069C>T and p.Q1313X) is located in coding exon 24 of the CFTR gene. In one study, this mutation was detected in homozygous state in a patient with pancreatic insufficiency and severe symptoms (Audrezet MP et. al. Hum. Molec Genet. 1993;2(1):51-54). This mutation is associated with decreased lung function (mean FEV 71%), elevated sweat chloride levels, pancreatic insufficiency, and pseudomonas (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167, Supplementary Table and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed July 27, 2015). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
Pathogenic (Apr 09, 2018)	no assertion criteria provided Method: literature only	CYSTIC FIBROSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027801.3 First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2018	Publications: PubMed (1) PubMed: 15024729 Comment on evidence: In a severely affected, pancreatic-insufficient patient with cystic fibrosis (CF; 219700), Audrezet et al. (1993) found homozygosity for a C-to-T transition at nucleotide 4069 in … (more) In a severely affected, pancreatic-insufficient patient with cystic fibrosis (CF; 219700), Audrezet et al. (1993) found homozygosity for a C-to-T transition at nucleotide 4069 in exon 21 converting gln1313 to a stop codon. (less)
Pathogenic (Sep 09, 2016)	no assertion criteria provided Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220756.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019	Publications: PubMed (1) PubMed: 23974870
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002075915.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

Variant summary: CFTR c.3937C>T (p.Gln1313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 250482 control chromosomes. c.3937C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, Audrezet_1993, Alonso_2007, Schrijver_2005, desGeorges_2004, Dorfman_2010, Krenkova_2012). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories and one expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Gln1313*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7683952, 22658665, 23974870). This variant is also known as c.4069C>T. ClinVar contains an entry for this variant (Variation ID: 7180). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Q1313* pathogenic mutation (also known as c.3937C>T, c.4069C>T and p.Q1313X) is located in coding exon 24 of the CFTR gene. In one study, this mutation was detected in homozygous state in a patient with pancreatic insufficiency and severe symptoms (Audrezet MP et. al. Hum. Molec Genet. 1993;2(1):51-54). This mutation is associated with decreased lung function (mean FEV 71%), elevated sweat chloride levels, pancreatic insufficiency, and pseudomonas (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167, Supplementary Table and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed July 27, 2015). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

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
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
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
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
Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis.	Sermet-Gaudelus I	American journal of respiratory and critical care medicine	2010	PMID: 20622033
Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?	Dorfman R	Clinical genetics	2010	PMID: 20059485
Distribution of CFTR mutations in Saguenay- Lac-Saint-Jean: proposal of a panel of mutations for population screening.	Madore AM	Genetics in medicine : official journal of the American College of Medical Genetics	2008	PMID: 18344710
Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.	Alonso MJ	Annals of human genetics	2007	PMID: 17331079
Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.	Schrijver I	The Journal of molecular diagnostics : JMD	2005	PMID: 15858154
High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France.	des Georges M	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2004	PMID: 15698946
Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms.	Audrézet MP	Human mutation	2004	PMID: 15024729
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.	Claustres M	Human mutation	2000	PMID: 10923036
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.	Cohn JA	The New England journal of medicine	1998	PMID: 9725922
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.	Yang Y	Human molecular genetics	1993	PMID: 7691345
Identification of 12 novel mutations in the CFTR gene.	Audrézet MP	Human molecular genetics	1993	PMID: 7683952
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
https://cftr2.org	-	-	-	-
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Text-mined citations for rs121909026 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.3937C>T (p.Gln1313Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121909026 ...