NM_000492.4(CFTR):c.1585-2A>T AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001328347.9

Allele description [Variation Report for NM_000492.4(CFTR):c.1585-2A>T]

NM_000492.4(CFTR):c.1585-2A>T

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674475:CFTR intron 11 enhancer [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1585-2A>T

HGVS:

NC_000007.14:g.117587737A>T
NG_016465.4:g.126954A>T
NG_056131.3:g.692A>T
NM_000492.4:c.1585-2A>TMANE SELECT
LRG_663t1:c.1585-2A>T
LRG_663:g.126954A>T
NC_000007.13:g.117227791A>T
NM_000492.3:c.1585-2A>T

Links:

dbSNP: rs397508233

NCBI 1000 Genomes Browser:

rs397508233

Molecular consequence:

NM_000492.4:c.1585-2A>T - 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
SCV001519433	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 9, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002150700	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16199547, 1695717, 7691345, 9725922, 11788090, 25066652, 28492532
SCV002705649	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 9, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25066652, 32730979 Citation Link,
SCV004047197	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	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	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sequencing as a first-line methodology for cystic fibrosis carrier screening.

Beauchamp KA, Johansen Taber KA, Grauman PV, Spurka L, Lim-Harashima J, Svenson A, Goldberg JD, Muzzey D.

Genet Med. 2019 Nov;21(11):2569-2576. doi: 10.1038/s41436-019-0525-y. Epub 2019 Apr 30. Erratum in: Genet Med. 2019 Oct;21(10):2407-2408. doi: 10.1038/s41436-019-0543-9.

PubMed [citation]

PMID:: 31036917
PMCID:: PMC6831513

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 (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001519433.1

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

Description

Variant summary: CFTR c.1585-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates/or strengthens a cryptic 5 donor site. Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250846 control chromosomes (gnomAD). c.1585-2A>T has been reported in the literature in an individual undergoing carrier screening (Beauchamp _2019). This report however, does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another nucleotide change in the same location (c.1585-2A>G) has been reported as pathogenic in our internal database and in ClinVar. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was 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, SCV002150700.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change affects an acceptor splice site in intron 11 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 individual(s) with cystic fibrosis (PMID: 11788090). ClinVar contains an entry for this variant (Variation ID: 1027585). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25066652). 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, SCV002705649.2

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

Description

The c.1585-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 12 in the CFTR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, based on available data in the literature, the in-frame transcript is unlikely to occur. In one minigene expression assay, 5 different variants were tested at this acceptor site, and none of them resulted in the in-frame transcript (Sharma N. et al. Hum Mutat 2014 Oct;35(10):1249-59). Another study found that a different alteration at this position, c.1585-2A>G, resulted in skipping of exon 12 and retention of 6 nucleotides in intron 11 (both out-of-frame transcripts). The presence of these two transcripts was confirmed in total RNA obtained from a patient with c.1585-2A>G (Silva IAL et al. Biochim Biophys Acta Mol Basis Dis 2020 11;1866(11):165905). In the same minigene assay, a common mutation c.1585-1G>A (1717-1G>A), resulted in skipping of exon 12 and a deletion of 1 nucleotide in exon 12. Further, analysis of RNA from nasal epithelial cells revealed that c.1585-1G>A resulted in skipping of exon 12 in 3 patients (Hull J. et al. Hum Mol Genet 1993 Jun;2(6):689-92). The c.1585-2A>T variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be 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 Neuberg Centre For Genomic Medicine, NCGM, SCV004047197.1

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

Description

The splice site c.1585-2A>T variant in CFTR gene has been reported in ClinVar as Likely Pathogenic. The c.1585-2A>T variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic.

#	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

Last Updated: Jan 13, 2025

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Relating variation to medicine