NM_000492.4(CFTR):c.2490+1G>A AND Cystic fibrosis

Germline classification:: Pathogenic (8 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:: RCV000007595.30

Allele description [Variation Report for NM_000492.4(CFTR):c.2490+1G>A]

NM_000492.4(CFTR):c.2490+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.2490+1G>A

Other names:

2622 + 1 G -> A; 2622+1G->A

HGVS:

NC_000007.14:g.117592658G>A
NG_016465.4:g.131875G>A
NM_000492.4:c.2490+1G>AMANE SELECT
LRG_663t1:c.2490+1G>A
LRG_663:g.131875G>A
NC_000007.13:g.117232712G>A
NG_016465.3:g.131875G>A
NM_000492.3:c.2490+1G>A

Nucleotide change:

IVS13, G-A, +1

Links:

OMIM: 602421.0071; dbSNP: rs141158996

NCBI 1000 Genomes Browser:

rs141158996

Molecular consequence:

NM_000492.4:c.2490+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000027796	OMIM	no assertion criteria provided	Pathogenic (Apr 9, 2018)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000071455	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,
SCV000074614	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 16199547, 1695717, 7691345, 9725922, 7683952, 9239681, 12815607, 20059485, 23974870, 28492532
SCV000220959	Counsyl	no assertion criteria provided	Pathogenic (Jul 21, 2015)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20059485, 23974870, 7683952
SCV000696902	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 7, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12215837, 7683952, 24697796, 12815607, 23974870, 9239681 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001169549	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Jan 29, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV001176547	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 18, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23974870, 7683952 Citation Link,
SCV002507345	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 31, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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, curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms.

Audrézet MP, Chen JM, Raguénès O, Chuzhanova N, Giteau K, Le Maréchal C, Quéré I, Cooper DN, Férec C.

Hum Mutat. 2004 Apr;23(4):343-57.

PubMed [citation]

PMID:: 15024729

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 (15)

Details of each submission

From OMIM, SCV000027796.3

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

Description

In a 2-year-old child with cystic fibrosis (CF; 219700) who carried the delta-F508 mutation (602421.0001) and manifested classic symptoms of CF, namely, pancreatic insufficiency and pulmonary disease, Audrezet et al. (1993) detected on the other chromosome a G-to-A transition in the first nucleotide in the 5-prime splice site of intron 13. Audrezet et al. (1993) referred to this mutation as 2622 +1 G-to-A.

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

From CFTR2 - CFTR2, SCV000071455.4

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000074614.10

#	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 a donor splice site in intron 14 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 (rs141158996, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 7683952, 9239681, 12815607, 20059485, 23974870). This variant is also known as 2622+1G>A. ClinVar contains an entry for this variant (Variation ID: 7175). 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 Counsyl, SCV000220959.2

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696902.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: The CFTR c.2490+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict the variant to abolish the canonical splice donor site. This variant was found in 2/109598 control chromosomes at a frequency of 0.0000182, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been cited in numerous classic CF patients in the literature in trans with pathogenic variants, including deltaF508. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely 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 CFTR-France, SCV001169549.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	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 Ambry Genetics, SCV001176547.4

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

Description

The c.2490+1G>A intronic pathogenic mutation (also known as 2622+1G>A) results from a G to A one nucleotide after coding exon 14 of the CFTR gene. This mutation was first described in an affected two-year-old with cystic fibrosis, including pancreatic insufficiency and pulmonary disease, in conjunction with p.F508del (Audrézet MP et al. Hum. Mol. Genet., 1993 Jan;2:51-4). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and an increased rate of 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 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 Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV002507345.1

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

#	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: Oct 26, 2024

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