VCV000007186.21 - ClinVar

NM_000492.4(CFTR):c.274G>T (p.Glu92Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

13 submissions

12 submitters

5 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.274G>T (p.Glu92Ter)

Variation ID: 7186 Accession: VCV000007186.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117530899 (GRCh38) [ NCBI UCSC ] 7: 117170953 (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	Oct 11, 2015	May 1, 2024	Mar 17, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.274G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Glu92Ter	nonsense
NC_000007.14:g.117530899G>T
NC_000007.13:g.117170953G>T
NG_016465.4:g.70116G>T
LRG_663:g.70116G>T
LRG_663t1:c.274G>T	LRG_663p1:p.Glu92Ter

... more HGVS ... less HGVS

Protein change

E92*

Other names

Canonical SPDI

NC_000007.14:117530898:G: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), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA325576 OMIM: 602421.0082 dbSNP: rs121908751 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	3835	5214

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 (9)	reviewed by expert panel	Mar 17, 2017	RCV000007606.22
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	-	RCV001004423.1
CFTR-related disorder Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2018	RCV001009515.1
CFTR-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 17, 2017	RCV001826443.1
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Jul 31, 2023	RCV003473036.1

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: SCV000071538.4 First in ClinVar: Oct 18, 2013 Last updated: Jan 06, 2018	Other databases https://cftr2.org https://cftr2.org
Pathogenic (Jul 31, 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: SCV000696921.1 First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018	Publications: PubMed (3) PubMed: 23276700‚ 7541274‚ 23974870 Comment: Variant summary: The CFTR c.274G>T (p.Glu92X) variant involves the alteration of a conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. … (more) Variant summary: The CFTR c.274G>T (p.Glu92X) variant involves the alteration of a conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. A functional study showed that it affects the 3 splice site of exon 4 and creates an in-frame stop codon and concluded this variant to determine pancreatic insufficiency (Will_JCI_1993). The variant of interest has not been found in a large, broad control population, ExAC in 0.0000047, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant was reported in multiple CF patients (Sosnay_Nature Genetics_2013, Will_JCI_1993). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Dec 09, 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: SCV001194021.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (1) PubMed: 23974870 Comment: NM_000492.3(CFTR):c.274G>T(E92) 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.274G>T(E92) 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.274G>T(E92*) 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 (Nov 05, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: unknown	Mendelics Accession: SCV000886217.2 First in ClinVar: Jan 06, 2018 Last updated: Dec 11, 2022
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: SCV001163467.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (Jan 29, 2018)	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	cystic fibrosis CFTR-related disorders Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169610.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Comment: the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
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: SCV002573831.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a … (more) This variant was identified in 2 unrelated patients 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, PS3_SUP, PM2_SUP, PM3_STR (less) Number of individuals with the variant: 2
Pathogenic (Nov 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV003839132.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Jul 31, 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: SCV004213449.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Nov 24, 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: SCV001585090.4 First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 1695717‚ 7691345‚ 9725922‚ 7512993‚ 23974870‚ 7525450‚ 15482777‚ 21783433‚ 22658665‚ 24586523 Comment: This sequence change creates a premature translational stop signal (p.Glu92) 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.Glu92) 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 (rs121908751, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 7512993, 23974870). ClinVar contains an entry for this variant (Variation ID: 7186). This variant disrupts the p.Arg117 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7525450, 15482777, 21783433, 22658665, 23974870, 24586523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 22, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002752116.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 23974870‚ 7512993‚ 7541274 Comment: The p.E92* pathogenic mutation (also known as c.274G>T and c.406G>T) is located in coding exon 4 of the CFTR gene. This changes the amino acid … (more) The p.E92* pathogenic mutation (also known as c.274G>T and c.406G>T) is located in coding exon 4 of the CFTR gene. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. Since this nucleotide is in the first position of coding exon 4, splicing effects have also been observed (Will K et al. J. Clin. Invest., 1994 Apr;93:1852-9; Will K et al. Hum. Mutat., 1995;5:210-20).This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 08/22/2022). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 (Apr 01, 1994)	no assertion criteria provided Method: literature only	CYSTIC FIBROSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027807.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2018	Publications: PubMed (1) PubMed: 7512993 Comment on evidence: In each of 4 German patients with cystic fibrosis (CF; 219700), Will et al. (1994) found a G-to-T transversion that affected the first base of … (more) In each of 4 German patients with cystic fibrosis (CF; 219700), Will et al. (1994) found a G-to-T transversion that affected the first base of exon 4 and created a termination codon glu92-to-ter. Lymphocyte RNA of patients heterozygous for the E92X mutation were found to contain the wildtype sequence and a differentially spliced isoform lacking exon 4. On the other hand, RNA derived from nasal epithelial cells of these patients showed a third fragment of longer length. Sequencing revealed the presence of E92X and an additional 183-bp fragment, inserted between exons 3 and 4. The 183-bp sequence was mapped to intron 3 of the CFTR gene. It was flanked by acceptor and donor splice sites. Will et al. (1994) concluded that the 183-bp fragment in intron 3 is a cryptic CFTR exon that can be activated in epithelial cells by the presence of the E92X mutation. E92X abolishes correctly spliced CFTR mRNA and leads to severe cystic fibrosis. (less)
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002080112.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
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Comment:

Variant summary: The CFTR c.274G>T (p.Glu92X) variant involves the alteration of a conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. A functional study showed that it affects the 3 splice site of exon 4 and creates an in-frame stop codon and concluded this variant to determine pancreatic insufficiency (Will_JCI_1993). The variant of interest has not been found in a large, broad control population, ExAC in 0.0000047, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant was reported in multiple CF patients (Sosnay_Nature Genetics_2013, Will_JCI_1993). 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.274G>T(E92*) 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.274G>T(E92*) 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:

This variant was identified in 2 unrelated patients 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, PS3_SUP, PM2_SUP, PM3_STR

Comment:

This sequence change creates a premature translational stop signal (p.Glu92*) 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 (rs121908751, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 7512993, 23974870). ClinVar contains an entry for this variant (Variation ID: 7186). This variant disrupts the p.Arg117 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7525450, 15482777, 21783433, 22658665, 23974870, 24586523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.E92* pathogenic mutation (also known as c.274G>T and c.406G>T) is located in coding exon 4 of the CFTR gene. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. Since this nucleotide is in the first position of coding exon 4, splicing effects have also been observed (Will K et al. J. Clin. Invest., 1994 Apr;93:1852-9; Will K et al. Hum. Mutat., 1995;5:210-20).This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 08/22/2022). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients.	Ziętkiewicz E	PloS one	2014	PMID: 24586523
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
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
The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization.	Wong LJ	Fertility and sterility	2004	PMID: 15482777
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.	Cohn JA	The New England journal of medicine	1998	PMID: 9725922
Transcript analysis of CFTR nonsense mutations in lymphocytes and nasal epithelial cells from cystic fibrosis patients.	Will K	Human mutation	1995	PMID: 7541274
Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients.	Dörk T	Human genetics	1994	PMID: 7525450
A novel exon in the cystic fibrosis transmembrane conductance regulator gene activated by the nonsense mutation E92X in airway epithelial cells of patients with cystic fibrosis.	Will K	The Journal of clinical investigation	1994	PMID: 7512993
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.	Yang Y	Human molecular genetics	1993	PMID: 7691345
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 rs121908751 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.274G>T (p.Glu92Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908751 ...