NM_000492.4(CFTR):c.2875del (p.Ala959fs) 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:: RCV000056373.21

Allele description [Variation Report for NM_000492.4(CFTR):c.2875del (p.Ala959fs)]

NM_000492.4(CFTR):c.2875del (p.Ala959fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.2875del (p.Ala959fs)

Other names:

3007delG

HGVS:

NC_000007.14:g.117603749del
NG_016465.4:g.142966del
NM_000492.4:c.2875delMANE SELECT
NP_000483.3:p.Ala959fs
NP_000483.3:p.Ala959fs
LRG_663t1:c.2875del
LRG_663:g.142966del
LRG_663p1:p.Ala959fs
NC_000007.13:g.117243803del
NM_000492.3:c.2875del
NM_000492.3:c.2875delG
p.Ala959HisfsX9

Protein change:

A959fs

Links:

dbSNP: rs397508447

NCBI 1000 Genomes Browser:

rs397508447

Molecular consequence:

NM_000492.4:c.2875del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000071478	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,
SCV000220800	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Oct 14, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 7530553, 20932301, 23974870, 22658665 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000916184	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Nov 2, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12815607, 15698946, 10923036, 23974870, 7530553, 20059485 Citation Link,
SCV001169524	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]
SCV001425419	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 22, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002230780	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23974870, 1695717, 7691345, 9725922, 28492532
SCV002573833	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2022)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV005107472	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 11, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients.

Green DM, McDougal KE, Blackman SM, Sosnay PR, Henderson LB, Naughton KM, Collaco JM, Cutting GR.

Respir Res. 2010 Oct 8;11:140. doi: 10.1186/1465-9921-11-140.

PubMed [citation]

PMID:: 20932301
PMCID:: PMC2964615

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis.

Ooi CY, Durie PR.

J Cyst Fibros. 2012 Sep;11(5):355-62. doi: 10.1016/j.jcf.2012.05.001. Epub 2012 Jun 2. Review.

PubMed [citation]

PMID:: 22658665

See all PubMed Citations (14)

Details of each submission

From CFTR2 - CFTR2, SCV000071478.4

#	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 Counsyl, SCV000220800.2

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

#	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 Illumina Laboratory Services, Illumina, SCV000916184.1

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

Description

The CFTR c.2875delG (p.Ala959HisfsTer9) variant, also referred to in the literature as c.3007delG, results in a frameshift and a premature truncation of the protein. This variant is widely reported in the literature and is classified as a cystic fibrosis (CF)-causing mutation according to the CFTR2 mutation database (www.cftr2.org). The database states the mutation has been observed in 40 CF individuals. Across a selection of the available literature, the p.Ala959HisfsTer9 variant was found in three compound heterozygous CF probands, in seven heterozygous probands with CF or congenital bilateral absence of vas deferens (CBAVD) and in 31 additional proband alleles (Mercier et al. 1994; Claustres et al. 2000; Scotet et al. 2003; des Georges et al. 2004; Dorfman et al. 2010; Sosnay et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project but this is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Based on the collective evidence and the potential impact of frameshift variants, the p.Ala959HisfsTer9 variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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, SCV001169524.1

#	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 Johns Hopkins Genomics, Johns Hopkins University, SCV001425419.1

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

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002230780.3

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53583). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 23974870). This variant is present in population databases (rs397508447, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ala959Hisfs*9) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922).

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002573833.1

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

Description

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1, PM2_SUP, PM3_VSTR

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

From Ambry Genetics, SCV005107472.1

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

Description

The c.2875delG pathogenic mutation, located in coding exon 17 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 2875, causing a translational frameshift with a predicted alternate stop codon (p.A959Hfs*9). This alteration is associated with elevated sweat chloride levels, decreased lung function, pancreatic insufficiency, and Pseudomonas infection (Sosnay PR, Nat. Genet. 2013 Oct; 45(10):1160-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted 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

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