NM_000492.4(CFTR):c.3659del (p.Thr1220fs) AND Cystic fibrosis

Germline classification:: Pathogenic (9 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:: RCV000007544.28

Allele description [Variation Report for NM_000492.4(CFTR):c.3659del (p.Thr1220fs)]

NM_000492.4(CFTR):c.3659del (p.Thr1220fs)

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.3659del (p.Thr1220fs)

Other names:

3659delC; 3791delC; p.Thr1220Lysfs*8

HGVS:

NC_000007.14:g.117627712del
NG_016465.4:g.166929del
NM_000492.4:c.3659delMANE SELECT
NP_000483.3:p.Thr1220fs
LRG_663t1:c.3659del
LRG_663:g.166929del
NC_000007.13:g.117267766del
NC_000007.13:g.117267766delC
NG_016465.1:g.152750del
NM_000492.3:c.3659delC
NP_000483.3:p.Thr1220fs
p.Thr1220LysfsX8

Links:

OMIM: 602421.0020; dbSNP: rs121908811

NCBI 1000 Genomes Browser:

rs121908811

Molecular consequence:

NM_000492.4:c.3659del - 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
SCV000027745	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1990)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000071480	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,
SCV000886227	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Nov 5, 2018)	unknown	clinical testing	Citation Link,
SCV001169299	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]
SCV001193907	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,
SCV001425440	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 24, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001442633	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 12, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002228111	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 28, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1695717, 7691345, 9725922, 9150159, 23261175, 23974870, 28492532
SCV002613471	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 26, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
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
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

Citations

PubMed

Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.

Kerem BS, Zielenski J, Markiewicz D, Bozon D, Gazit E, Yahav J, Kennedy D, Riordan JR, Collins FS, Rommens JM, et al.

Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447-51.

PubMed [citation]

PMID:: 2236053
PMCID:: PMC54973

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

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000027745.2

#	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), Kerem et al. (1990) detected deletion of a C at nucleotide 3659 in exon 19 of the (3659delC) CFTR gene resulting in 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, SCV000071480.4

#	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, SCV000886227.2

#	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, SCV001169299.1

#	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., SCV001193907.1

#	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.3659delC(T1220Kfs*8, aka 3791delC) 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.3659delC(T1220Kfs*8, aka 3791delC) 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 Johns Hopkins Genomics, Johns Hopkins University, SCV001425440.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442633.1

#	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.3659delC (p.Thr1220LysfsX8) 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. The variant allele was found at a frequency of 4e-06 in 250166 control chromosomes. c.3659delC has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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 Invitae, SCV002228111.3

#	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 creates a premature translational stop signal (p.Thr1220Lysfs*8) 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 (rs121908811, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 9150159, 23261175, 23974870). This variant is also known as c.3791delC. ClinVar contains an entry for this variant (Variation ID: 7124). 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 Ambry Genetics, SCV002613471.2

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

Description

The c.3659delC pathogenic mutation, located in coding exon 22 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 3659, causing a translational frameshift with a predicted alternate stop codon (p.T1220Kfs*8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 07/26/2022). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 8, 2024

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