NM_000492.4(CFTR):c.2423_2424dup (p.Ser809fs) AND Cystic fibrosis

Germline classification:: Pathogenic (5 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:: RCV000190991.16

Allele description [Variation Report for NM_000492.4(CFTR):c.2423_2424dup (p.Ser809fs)]

NM_000492.4(CFTR):c.2423_2424dup (p.Ser809fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.2423_2424dup (p.Ser809fs)

Other names:

2556insAT

HGVS:

NC_000007.14:g.117592584AT[5]
NG_016465.4:g.131801AT[5]
NM_000492.4:c.2423_2424dupMANE SELECT
NP_000483.3:p.Ser809fs
LRG_663:g.131801AT[5]
NC_000007.13:g.117232637_117232638insAT
NC_000007.13:g.117232638AT[5]
NM_000492.3:c.2423_2424dupAT
NM_000492.3:c.2424_2425insAT
p.Ser809IlefsX13

Protein change:

S809fs

Links:

OMIM: 602421.0019; dbSNP: rs387906359

NCBI 1000 Genomes Browser:

rs387906359

Molecular consequence:

NM_000492.4:c.2423_2424dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

Recent activity

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conserved oligomeric Golgi complex subunit 5-like [Tripterygium wilfordii]
conserved oligomeric Golgi complex subunit 5-like [Tripterygium wilfordii]
gi|1954758745|ref|XP_038684184.1|

Protein
RecName: Full=Creatine kinase U-type, mitochondrial; AltName: Full=Acidic-type m...
RecName: Full=Creatine kinase U-type, mitochondrial; AltName: Full=Acidic-type mitochondrial creatine kinase; Short=Mia-CK; AltName: Full=Ubiquitous mitochondrial creatine kinase; Short=U-MtCK; Flags: Precursor
gi|125315|sp|P12532.1|KCRU_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027742	OMIM	no assertion criteria provided	Pathogenic (Apr 12, 1990)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000245918	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,
SCV001426818	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7521710, 30996306, 30888834, 1691449 Citation Link,
SCV001580683	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 29, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1695717, 7691345, 9725922, 1691449, 28492532
SCV002737401	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 25, 2022)	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
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

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

Sensitivity of single-strand conformation polymorphism and heteroduplex method for mutation detection in the cystic fibrosis gene.

Ravnik-Glavac M, Glavac D, Dean M.

Hum Mol Genet. 1994 May;3(5):801-7.

PubMed [citation]

PMID:: 7521710

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000027742.2

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

Description

In a patient with cystic fibrosis (CF; 219700), White et al. (1990) detected insertion of 2 nucleotides, AT, after nucleotide 2566 (2566insAT) in exon 13 of the CFTR gene, responsible for a frameshift.

#	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, SCV000245918.2

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001426818.3

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

Description

Variant summary: CFTR c.2423_2424dupAT (p.Ser809IlefsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. This variant is also reported as legacy name 2556insAT, and can be referred to as c.2424_2425dupAT, c.2421_2422dupAT, and c.2422_2423insAT. The variant was absent in 179966 control chromosomes (gnomAD). c.2423_2424dupAT has been reported in the literature and in CF patient databases in individuals affected with Cystic Fibrosis (e.g. White_1990, CFTR2 database). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001580683.4

#	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. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant has been observed in individual(s) with clinical features of cystic fibrosis (CF) (PMID: 1691449). This variant is also known as CFIns2566 and 2556insAT. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser809Ilefs*13) in the CFTR gene. It is expected to result in an absent or disrupted protein product.

#	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, SCV002737401.2

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

Description

The c.2423_2424dupAT pathogenic mutation (also known as CFTR ins2556insAT, c.2424_2425dupAT, c.2421_2422dupAT, and c.2422_2423insAT) is located in coding exon 14 of the CFTR gene and results from a duplication of AT at nucleotide position 2423, causing a translational frameshift with a predicted alternate stop codon (p.S809Ifs*13). This alteration was described in an individual with features of cystic fibrosis or a CFTR-related disorder (White MB et al. Nature, 1990 Apr;344:665-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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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