NM_000492.4(CFTR):c.274-1G>A AND Cystic fibrosis

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 17, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000056370.16

Allele description [Variation Report for NM_000492.4(CFTR):c.274-1G>A]

NM_000492.4(CFTR):c.274-1G>A

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.274-1G>A

Other names:

406-1G>A; 406-1G->A

HGVS:

NC_000007.14:g.117530898G>A
NG_016465.4:g.70115G>A
NM_000492.4:c.274-1G>AMANE SELECT
LRG_663t1:c.274-1G>A
LRG_663:g.70115G>A
NC_000007.13:g.117170952G>A
NM_000492.3:c.274-1G>A

Links:

dbSNP: rs121908792

NCBI 1000 Genomes Browser:

rs121908792

Molecular consequence:

NM_000492.4:c.274-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000071460	CFTR2 - CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Mar 17, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000696918	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 24, 2017)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 23687349, 16980811, 23810505, 17331079, 15858154, 15365999, 10798368, 16049310, 21796730, 11668613, 12007216 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001193957	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 4, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21416780, 17331079, 11668613, 23974870, 10798368 Citation Link,
SCV001578210	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 16199547, 1695717, 7691345, 9725922, 10798368, 11668613, 15365999, 23974870, 26708955, 28492532
SCV002747515	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 3, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10798368, 11668613, 23974870 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR.

Trujillano D, Ramos MD, González J, Tornador C, Sotillo F, Escaramis G, Ossowski S, Armengol L, Casals T, Estivill X.

J Med Genet. 2013 Jul;50(7):455-62. doi: 10.1136/jmedgenet-2013-101602. Epub 2013 May 17.

PubMed [citation]

PMID:: 23687349

Comprehensive genetic analysis of the cystic fibrosis transmembrane conductance regulator from dried blood specimens--implications for newborn screening.

Kammesheidt A, Kharrazi M, Graham S, Young S, Pearl M, Dunlop C, Keiles S.

Genet Med. 2006 Sep;8(9):557-62.

PubMed [citation]

PMID:: 16980811

See all PubMed Citations (19)

Details of each submission

From CFTR2 - CFTR2, SCV000071460.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696918.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: The CFTR c.274-1G>A variant (alternatively also known as 406-1G>A) involves the alteration of a highly conserved nucleotide in the consensus splice acceptor site in intron 3, therefore it is expected to cause aberrant splicing. 5/5 splice prediction tools also predict the abrogation of the splice acceptor site. Thus this variant is very likely to result in loss of function which is a known disease mechanism in CF. This variant was found in 1/116316 control chromosomes from ExAC at a frequency of 0.0000086, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant is found in several CF patients, mainly in Hispanic CF population in compound heterozygous state with other likely or known pathogenic variants. In a large CF population from North American and Europe, its allele frequency was found to be at 0.03% (Sosnay_2013). Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193957.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

NM_000492.3(CFTR):c.274-1G>A(aka 406-1G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 21416780, 17331079, 11668613, 23974870 and 10798368. Classification of NM_000492.3(CFTR):c.274-1G>A(aka 406-1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001578210.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change affects an acceptor splice site in intron 3 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs121908792, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 10798368, 11668613, 15365999, 23974870, 26708955). This variant is also known as c.406-1G>A. ClinVar contains an entry for this variant (Variation ID: 48680). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002747515.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.274-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 4 of the CFTR gene. This mutation has been reported in multiple cystic fibrosis (CF) patients with a second mutation confirmed in trans; it is associated with elevated sweat chloride levels, pancreatic insufficiency, and Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine