NM_000492.4(CFTR):c.165-1G>A AND Cystic fibrosis

Germline classification:: Pathogenic (7 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:: RCV000046382.14

Allele description [Variation Report for NM_000492.4(CFTR):c.165-1G>A]

NM_000492.4(CFTR):c.165-1G>A

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC113664106:CFTR intron 2 DNase I hypersensitive site [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.165-1G>A

Other names:

297-1G->A

HGVS:

NC_000007.14:g.117509033G>A
NG_016465.4:g.48250G>A
NG_062452.1:g.671G>A
NM_000492.4:c.165-1G>AMANE SELECT
LRG_663t1:c.165-1G>A
LRG_663:g.48250G>A
NC_000007.13:g.117149087G>A
NM_000492.3:c.165-1G>A

Links:

dbSNP: rs397508249

NCBI 1000 Genomes Browser:

rs397508249

Molecular consequence:

NM_000492.4:c.165-1G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000245916	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,
SCV000696859	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 28, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26098992, 16980811, 10798368 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000790424	Counsyl	no assertion criteria provided	Pathogenic (Mar 24, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10798368, 16980811
SCV002705563	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 14, 2018)	germline	clinical testing	Citation Link,
SCV003219444	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16199547, 1695717, 7691345, 9725922, 10798368, 12000363, 16980811, 26098992, 28492532
SCV004239026	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26098992, 25741868
SCV004847364	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10798368, 16980811, 26098992, 25741868

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

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.

Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR.

Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.

PubMed [citation]

PMID:: 23974870
PMCID:: PMC3874936

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (11)

Details of each submission

From CFTR2 - CFTR2, SCV000245916.2

#	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, SCV000696859.1

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

Description

Variant summary: The CFTR c.165-1G>A (a.k.a. IVS2-1G>A, 297-1G>A) variant involves the alteration of a conserved intronic nucleotide, at a location known to affect splicing, with 5/5 splice prediction tools predicting alterations to normal splicing and the removal of two ESE binding sites, although these predictions have yet to be functionally assessed. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals as compound heterozytoges via publications, In addition, multiple databases/clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest 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 Counsyl, SCV000790424.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Ambry Genetics, SCV002705563.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.165-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 3 of the CFTR gene. This mutation was first reported in the literature in a patient with meconium ileus, severe lung disease, and pancreatic insufficiency, who also carried a p.F508del mutation on the paternal allele (Orozco L et al. Hum Genet. 2000;106:360-5). 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 likely 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003219444.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change affects an acceptor splice site in intron 2 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 10798368, 12000363, 16980811, 26098992). This variant is also known as 297-1G>A. ClinVar contains an entry for this variant (Variation ID: 53314). 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 Johns Hopkins Genomics, Johns Hopkins University, SCV004239026.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847364.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.165-1G>A variant in CFTR has been reported in the compound heterozygous state with another pathogenic variant in CFTR in at least 3 individuals with clinical features of cystic fibrosis (Orozco 2000 PMID: 10798368, Kammesheidt 2006 PMID: 16980811, Kay 2015 PMID: 26098992). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 53314) and was absent from large population studies (gnomAD, v.3.1.2). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting.

#	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

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