NM_000492.4(CFTR):c.1135G>T (p.Glu379Ter) AND Cystic fibrosis

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jul 31, 2020
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:: RCV000665109.9

Allele description [Variation Report for NM_000492.4(CFTR):c.1135G>T (p.Glu379Ter)]

NM_000492.4(CFTR):c.1135G>T (p.Glu379Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1135G>T (p.Glu379Ter)

Other names:

p.Glu379X; E379X

HGVS:

NC_000007.14:g.117542034G>T
NG_016465.4:g.81251G>T
NM_000492.4:c.1135G>TMANE SELECT
NP_000483.3:p.Glu379Ter
NP_000483.3:p.Glu379Ter
LRG_663t1:c.1135G>T
LRG_663:g.81251G>T
LRG_663p1:p.Glu379Ter
NC_000007.13:g.117182088G>T
NM_000492.3:c.1135G>T

Protein change:

E379*

Links:

dbSNP: rs397508165

NCBI 1000 Genomes Browser:

rs397508165

Molecular consequence:

NM_000492.4:c.1135G>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000789175	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jan 16, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001981554	CFTR2	reviewed by expert panel (Submitter's publication and website)	Pathogenic (Jul 31, 2020)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002140901	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 19, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1695717, 7691345, 9725922, 25910067, 31245908, 28492532
SCV002573799	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]
SCV002611913	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Dec 5, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25910067, 31245908, 31523618 Citation Link

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
not provided	unknown	yes	6	not provided	not provided	not provided	not provided	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	1	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 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 (9)

Details of each submission

From Counsyl, SCV000789175.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR2, SCV001981554.1

#	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 Invitae, SCV002140901.3

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

Description

This sequence change creates a premature translational stop signal (p.Glu379*) 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). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with CFTR-related conditions (PMID: 25910067, 31245908). ClinVar contains an entry for this variant (Variation ID: 53200). This variant is not present in population databases (ExAC no frequency).

#	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, SCV002573799.1

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

Description

This variant was identified in 6 unrelated patients 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_STR, PP4

#	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		6	not provided	not provided	not provided

From Ambry Genetics, SCV002611913.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The p.E379* pathogenic mutation (also known as c.1135G>T), located in coding exon 9 of the CFTR gene, results from a G to T substitution at nucleotide position 1135. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This variant has been reported in a cohort of individuals with cystic fibrosis (CF) (Petrova G et al. Mol Genet Genomic Med, 2019 Aug;7:e696) and was identified in conjunction with p.F508del in a North Macedonian individual with CF (Terzic M et al. Balkan J. Med. Genet., 2019 Jun;22:35-40). 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	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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