VCV000984347.8 - ClinVar

NM_000492.4(CFTR):c.1540G>T (p.Glu514Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

5 out of 5 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.1540G>T (p.Glu514Ter)

Variation ID: 984347 Accession: VCV000984347.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117559611 (GRCh38) [ NCBI UCSC ] 7: 117199665 (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	Nov 12, 2020	Apr 4, 2026	Aug 5, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1540G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Glu514Ter	nonsense
NM_000492.3:c.1540G>T
NC_000007.14:g.117559611G>T
NC_000007.13:g.117199665G>T
NG_016465.4:g.98828G>T
LRG_663:g.98828G>T

... more HGVS ... less HGVS

Protein change

E514*

Other names

Canonical SPDI

NC_000007.14:117559610:G:T

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: CA368984808 dbSNP: rs1799425190 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		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	3898	6387
CFTR-AS1	-	-	-	GRCh38	-	628

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 (3)	criteria provided, multiple submitters, no conflicts	Sep 5, 2022	RCV001264357.7
CFTR-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Aug 5, 2025	RCV006644715.1
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Likely pathogenic (1)	criteria provided, single submitter	Apr 23, 2024	RCV005040108.1

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Apr 08, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Cystic fibrosis	Myriad Genetics, Inc. Accession: SCV001442461.1 First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020 Comment: NM_000492.3(CFTR):c.1540G>T(E514) is expected to be pathogenic in the context of cystic fibrosis. This variant is predicted to lead to an abnormal or absent protein product … (more) NM_000492.3(CFTR):c.1540G>T(E514) is expected to be pathogenic in the context of cystic fibrosis. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in CFTR, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening. (less)	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Sep 05, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cystic fibrosis	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002573928.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: show 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, PM2_SUP (less) Observation: 1 Collection method: curation Allele origin: unknown Affected status: yes more Observation 1 Collection method: curation Allele origin: unknown Affected status: yes Number of individuals with the variant: 2

Pathogenic (Feb 06, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cystic fibrosis	Ambry Genetics Accession: SCV002705072.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: show The p.E514* pathogenic mutation (also known as c.1540G>T), located in coding exon 11 of the CFTR gene, results from a G to T substitution at nucleotide position 1540. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Apr 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary pancreatitis Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Fulgent Genetics, Fulgent Genetics Accession: SCV005673327.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Aug 05, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	CFTR-related disorders	Natera, Inc. Accession: SCV007536598.1 First in ClinVar: Apr 04, 2026 Last updated: Apr 04, 2026	Comment: show The c.1540G>T variant in CFTR is a nonsense variant predicted to introduce a stop codon at amino acid 514. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

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, PM2_SUP

Comment:

The p.E514* pathogenic mutation (also known as c.1540G>T), located in coding exon 11 of the CFTR gene, results from a G to T substitution at nucleotide position 1540. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. 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).

Comment:

The c.1540G>T variant in CFTR is a nonsense variant predicted to introduce a stop codon at amino acid 514. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely Pathogenic.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1799425190 ...

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 Apr 13, 2026