VCV000053534.14 - ClinVar

NM_000492.4(CFTR):c.263T>G (p.Leu88Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

8 submissions

8 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.263T>G (p.Leu88Ter)

Variation ID: 53534 Accession: VCV000053534.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117509132 (GRCh38) [ NCBI UCSC ] 7: 117149186 (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	Feb 6, 2014	May 1, 2024	Mar 17, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.263T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Leu88Ter	nonsense
NC_000007.14:g.117509132T>G
NC_000007.13:g.117149186T>G
NG_016465.4:g.48349T>G
NG_062452.1:g.770T>G
LRG_663:g.48349T>G
LRG_663t1:c.263T>G	LRG_663p1:p.Leu88Ter

... more HGVS ... less HGVS

Protein change

L88*

Other names

Canonical SPDI

NC_000007.14:117509131:T:G

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA326876 dbSNP: rs397508412 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 (4)	reviewed by expert panel	Mar 17, 2017	RCV000046644.14
not specified	Pathogenic (1)	criteria provided, single submitter	May 25, 2018	RCV000781278.1
CFTR-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 17, 2017	RCV001835659.1
CFTR-related disorder Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	Aug 31, 2021	RCV002281549.1
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Sep 17, 2023	RCV003473490.1

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: SCV000677618.1 First in ClinVar: Dec 12, 2017 Last updated: Dec 12, 2017	Other databases https://cftr2.org https://cftr2.org
Pathogenic (Sep 17, 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: SCV004213383.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Oct 09, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002739702.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 1284542‚ 18955805‚ 23302613‚ 27806795‚ 7512860 Comment: The p.L88* pathogenic mutation (also known as c.263T>G), located in coding exon 3 of the CFTR gene, results from a T to G substitution at … (more) The p.L88* pathogenic mutation (also known as c.263T>G), located in coding exon 3 of the CFTR gene, results from a T to G substitution at nucleotide position 263. This changes the amino acid from a leucine to a stop codon within coding exon 3. This alteration and another nucleotide substitution with the same protein impact (c.263T>A) have been detected in patients reported to have cystic fibrosis with another pathogenic CFTR mutation reported as occurring in trans (Macek M et al. Hum. Mutat., 1992;1:501-2; Savov A et al. Hum. Mol. Genet., 1994 Jan;3:57-60; Ko JM et al. J. Korean Med. Sci., 2008 Oct;23:912-5). 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 (Aug 31, 2021)	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: SCV002570015.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022	Comment: the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Likely pathogenic (Mar 18, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000486032.2 First in ClinVar: Feb 06, 2014 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 8528204‚ 18955805‚ 23420618‚ 1284542‚ 23302613
Pathogenic (Nov 29, 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: SCV001580101.4 First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 1695717‚ 7691345‚ 9725922‚ 1284542‚ 18955805‚ 23302613 Comment: This sequence change creates a premature translational stop signal (p.Leu88) 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.Leu88) 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: 1284542, 18955805, 23302613). 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: 53534). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 25, 2018)	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: SCV000919191.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (3) PubMed: 8528204‚ 18955805‚ 27081564 Comment: Variant summary: CFTR c.263T>G (p.Leu88X) 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.263T>G (p.Leu88X) 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. The variant was absent in 245518 control chromosomes. c.263T>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Savov 1995, Ko 2008, Tian 2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002080101.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

The p.L88* pathogenic mutation (also known as c.263T>G), located in coding exon 3 of the CFTR gene, results from a T to G substitution at nucleotide position 263. This changes the amino acid from a leucine to a stop codon within coding exon 3. This alteration and another nucleotide substitution with the same protein impact (c.263T>A) have been detected in patients reported to have cystic fibrosis with another pathogenic CFTR mutation reported as occurring in trans (Macek M et al. Hum. Mutat., 1992;1:501-2; Savov A et al. Hum. Mol. Genet., 1994 Jan;3:57-60; Ko JM et al. J. Korean Med. Sci., 2008 Oct;23:912-5). 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.

Comment:

This sequence change creates a premature translational stop signal (p.Leu88*) 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: 1284542, 18955805, 23302613). 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: 53534). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: CFTR c.263T>G (p.Leu88X) 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. The variant was absent in 245518 control chromosomes. c.263T>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Savov 1995, Ko 2008, Tian 2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was 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
[Infantile cholestasis caused by CFTR mutation: case report and literature review].	Li L	Zhonghua er ke za zhi = Chinese journal of pediatrics	2016	PMID: 27806795
p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis.	Tian X	Human genome variation	2016	PMID: 27081564
Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level.	Aissat A	Human mutation	2013	PMID: 23420618
[Clinical manifestations and gene analysis of 2 Chinese children with cystic fibrosis].	Liu JR	Zhonghua er ke za zhi = Chinese journal of pediatrics	2012	PMID: 23302613
Identification of a novel mutation of CFTR gene in a Korean patient with cystic fibrosis.	Ko JM	Journal of Korean medical science	2008	PMID: 18955805
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.	Cohn JA	The New England journal of medicine	1998	PMID: 9725922
Double mutant alleles: are they rare?	Savov A	Human molecular genetics	1995	PMID: 8528204
Identification of six novel mutations in the CFTR gene of patients from Bulgaria by screening the twenty seven exons and exon/intron boundaries using DGGE and direct DNA sequencing.	Savov A	Human molecular genetics	1994	PMID: 7512860
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.	Yang Y	Human molecular genetics	1993	PMID: 7691345
Identification of a novel nonsense mutation (L88X) in exon 3 of the cystic fibrosis transmembrane conductance regulator gene in a native Korean cystic fibrosis chromosome.	Macek M Jr	Human mutation	1992	PMID: 1284542
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 rs397508412 ...

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Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.263T>G (p.Leu88Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397508412 ...