NM_000492.4(CFTR):c.1393-1G>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:: RCV000056347.22

Allele description [Variation Report for NM_000492.4(CFTR):c.1393-1G>A]

NM_000492.4(CFTR):c.1393-1G>A

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS1:CFTR antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1393-1G>A

Other names:

1525-1G->A

HGVS:

NC_000007.14:g.117559463G>A
NG_016465.4:g.98680G>A
NM_000492.4:c.1393-1G>AMANE SELECT
LRG_663t1:c.1393-1G>A
LRG_663:g.98680G>A
NC_000007.13:g.117199517G>A
NM_000492.3:c.1393-1G>A

Links:

dbSNP: rs397508200

NCBI 1000 Genomes Browser:

rs397508200

Molecular consequence:

NM_000492.4:c.1393-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

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
SCV000071451	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,
SCV000205857	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Oct 18, 2013)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23933162, 7682196, 12843337, 15088804, 16137181, 24033266
SCV000696839	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 26208274, 16436643, 18782298, 9003508, 12843337, 7573058, 9482579, 12007216 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001169562	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]
SCV001579489	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 16199547, 1695717, 7691345, 9725922, 7682196, 9239681, 9482579, 15727251, 17662673, 18373402, 18782298, 21198395, 21909392, 23933162, 25688174, 26208274, 26708955, 28492532
SCV002564583	Arcensus	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002696017	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 17, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12843337, 15088804, 16137181, 23933162, 7682196 Citation Link,
SCV005061397	Dr.Nikuei Genetic Center	no assertion criteria provided	Pathogenic	germline	clinical testing

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, research, curation
not provided	germline	not provided	1	1	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

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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (29)

Details of each submission

From CFTR2 - CFTR2, SCV000071451.4

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000205857.4

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

Description

The 1393-1G>A variant in CFTR causes cystic fibrosis when combined with another CF-causing variant. It has been previously identified in 2 homozygous and 3 comp ound heterozygous individuals with cystic fibrosis and was found to segregate wi th disease in 1 family member (Dork 1993, Ramalho 2003, Wahab 2004, Ashavaid 200 5, Nikolic 2013). It has not been identified in large population studies. This v ariant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent pro tein (Ramalho 2003). In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, absence from controls, and functional evidence.

#	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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696839.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: The c.1393-1G>A in CFTR gene is a splice-site variant that alters a highly conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical splicing acceptor sequence, although these predictions are yet to be confirmed by the functional studies. The variant is present in control dataset of ExAC at a low frequency of 0.000049 (6/121108 chrs tested) which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0129). This variant appears to be very common in Palestina (Siryani, 2015). The variant was found homozygously or in compound heterozygosity in multiple affected individuals with established dx of CF. Patients, homozygous for the variant of interest, presented with elevated sweat Cl- (ranging from 110 to 148 mmol/L) and PI. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was 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, SCV001169562.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001579489.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

This sequence change affects an acceptor splice site in intron 10 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 (rs397508200, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis and congenital bilateral absence of the vas deferens (PMID: 7682196, 9239681, 9482579, 15727251, 17662673, 18373402, 18782298, 21198395, 21909392, 23933162, 25688174, 26208274, 26708955). This variant is also known as c.1525-1G>A. ClinVar contains an entry for this variant (Variation ID: 53242). 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 Arcensus, SCV002564583.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002696017.2

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

Description

The c.1393-1G>A intronic pathogenic mutation (also known as 1525-1G>A) results from a G to A substitution one nucleotide upstream from coding exon 11 of the CFTR gene. This mutation was first reported in an Afghani individual with elevated sweat chloride levels and clinical features of cystic fibrosis (CF); however, a second CFTR alteration was not identified (Dörk T et al. Genomics, 1993 Mar;15:688-91). A Serbian individual homozygous for this mutation presented with liver steatosis at age 7 years and later developed respiratory symptoms; he had mild pancreatic insufficiency and elevated sweat chloride levels (Nikolic A et al. J. Cyst. Fibros., 2014 Jan;13:111-3). Splicing analysis in colonic biopsies from two related Pakistani individuals with CF with c.1393-1G>A and p.F508del demonstrated exon skipping or the use of alternative splice sites due to the intronic alteration. Furthermore, the same study demonstrated that CFTR mediated chloride secretion was absent in the colonic biopsies of the affected individuals (Ramalho AS et al. J. Med. Genet., 2003 Jul;40:e88). 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

From Dr.Nikuei Genetic Center, SCV005061397.1

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

#	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: Nov 24, 2024

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