NM_000492.3(CFTR):c.2175dup (p.Glu726Argfs) AND Cystic fibrosis

Germline classification:: Pathogenic (10 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:: RCV000007605.33

Allele description [Variation Report for NM_000492.3(CFTR):c.2175dup (p.Glu726Argfs)]

NM_000492.3(CFTR):c.2175dup (p.Glu726Argfs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.3(CFTR):c.2175dup (p.Glu726Argfs)

Other names:

2307insA

HGVS:

NC_000007.13:g.117232394_117232395insA
NC_000007.14:g.117592342dup
NG_016465.4:g.131559dup
NM_000492.4:c.2175dupMANE SELECT
NP_000483.3:p.Glu726fs
NP_000483.3:p.Glu726fs
LRG_663t1:c.2175dup
LRG_663:g.131559dup
LRG_663p1:p.Glu726fs
NC_000007.13:g.117232394_117232395insA
NC_000007.13:g.117232396dup
NC_000007.13:g.117232396dup
NC_000007.13:g.117232396dupA
NC_000007.14:g.117592342_117592343insA
NM_000492.3:c.2175dup
NM_000492.3:c.2175dupA
p.Glu726fs

Protein change:

E726fs

Links:

OMIM: 602421.0081; dbSNP: rs746418935

NCBI 1000 Genomes Browser:

rs746418935

Molecular consequence:

NM_000492.4:c.2175dup - 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
SCV000027806	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1993)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000071474	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,
SCV000886215	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Nov 5, 2018)	unknown	clinical testing	Citation Link,
SCV001169544	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]
SCV001193918	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 7, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001338858	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV001582512	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 29, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1695717, 7691345, 9725922, 7686423, 15371903, 18456578, 28492532
SCV002727273	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 24, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12007216, 23974870, 7686423, 9150159 Citation Link,
SCV004024551	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004847339	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7686423, 32674983, 15371903, 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, curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	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, phenotyping only

Citations

PubMed

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.

Claustres M, Thèze C, des Georges M, Baux D, Girodon E, Bienvenu T, Audrezet MP, Dugueperoux I, Férec C, Lalau G, Pagin A, Kitzis A, Thoreau V, Gaston V, Bieth E, Malinge MC, Reboul MP, Fergelot P, Lemonnier L, Mekki C, Fanen P, Bergougnoux A, et al.

Hum Mutat. 2017 Oct;38(10):1297-1315. doi: 10.1002/humu.23276. Epub 2017 Jun 28.

PubMed [citation]

PMID:: 28603918

A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.

Cutting GR, Kasch LM, Rosenstein BJ, Zielenski J, Tsui LC, Antonarakis SE, Kazazian HH Jr.

Nature. 1990 Jul 26;346(6282):366-9.

PubMed [citation]

PMID:: 1695717

See all PubMed Citations (13)

Details of each submission

From OMIM, SCV000027806.2

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

Description

By chemical mismatch cleavage in an African American patient with cystic fibrosis (CF; 219700), Smit et al. (1993) found homozygosity for insertion of an adenine after nucleotide 2307 in exon 13. The resulting shift of the reading frame at codon 726 introduced 2 consecutive stop codons at amino acid positions 729 and 730. To examine the mRNA level associated with the 2307insA mutation, RNA from nasal epithelial cells of the patient and a normal subject were reverse transcribed. Subsequent amplification of the cDNA demonstrated that the CFTR message level associated with 2307insA was markedly reduced compared to the normal control, while both the patient and the normal subject showed similar levels of expression.

#	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, SCV000071474.4

#	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 Mendelics, SCV000886215.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR-France, SCV001169544.1

#	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 Myriad Genetics, Inc., SCV001193918.2

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

Description

NM_000492.3(CFTR):c.2175dupA(E726Rfs*4, aka 2307insA) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.2175dupA(E726Rfs*4, aka 2307insA) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

#	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 GenomeConnect, ClinGen, SCV001338858.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpretted as Pathogenic and reported on 01-07-2016 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001582512.4

#	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 creates a premature translational stop signal (p.Glu726Argfs*4) 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). This variant is present in population databases (rs746418935, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7686423, 15371903, 18456578). It is commonly reported in individuals of African American ancestry (PMID: 7686423, 15371903, 18456578). This variant is also known as c.2307insA. ClinVar contains an entry for this variant (Variation ID: 7185). 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, SCV002727273.2

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

Description

The c.2175dupA pathogenic mutation, located in coding exon 14 of the CFTR gene, results from a duplication of A at nucleotide position 2175, causing a translational frameshift with a predicted alternate stop codon (p.E726Rfs*4). This mutation was described in the homozygous state in an African American individual with pancreatic insufficient cystic fibrosis, elevated sweat chloride levels, and severe lung disease (Smit LS et al. Hum. Mutat., 1993;2:148-51). The overall frequency of this allele in CF chromosomes has been observed at approximately 0.2%, with the highest occurrence in 2.0% of all African American CF chromosomes (Macek M et al. Am. J. Hum. Genet., 1997 May;60:1122-7; Bobadilla JL et al. Hum. Mutat., 2002 Jun;19:575-606). This pathogenic mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Of note, this alteration is also known as 2307insA in published literature. 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

From Johns Hopkins Genomics, Johns Hopkins University, SCV004024551.2

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847339.1

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

Description

The p.Glu726ArgfsX4 variant in CFTR is commonly reported in individuals of African American ancestry and has been identified in the homozygous or compound heterozygous state with other disease-causing variants in CFTR in at least 2 individuals with clinical features of cystic fibrosis (Smit 1993 PMID: 7686423, Sugarman 2004 PMID: 15371903, Souza 2020 PMID: 32674983). In addition, it has been found in 59 patients in the CFTR2 database, the majority of which are pancreatic insufficient. This variant has also been reported by other clinical laboratories in ClinVar ((Variation ID 7185) and has been identified in 0.02% (9/41432) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 726 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated 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, PM2_Supporting, PM3.

#	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: Nov 24, 2024

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