NM_000492.4(CFTR):c.1373del (p.Gly458fs) AND Cystic fibrosis

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 8, 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:: RCV000046285.15

Allele description [Variation Report for NM_000492.4(CFTR):c.1373del (p.Gly458fs)]

NM_000492.4(CFTR):c.1373del (p.Gly458fs)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS1:CFTR antisense RNA 1 [Gene - HGNC]

Variant type:

Deletion

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1373del (p.Gly458fs)

HGVS:

NC_000007.13:g.117188857del
NC_000007.14:g.117548804del
NG_016465.4:g.88021del
NM_000492.4:c.1373delMANE SELECT
NP_000483.3:p.Gly458fs
NP_000483.3:p.Gly458fs
LRG_663t1:c.1373del
LRG_663:g.88021del
LRG_663p1:p.Gly458fs
NC_000007.13:g.117188857del
NC_000007.13:g.117188858del
NC_000007.13:g.117188858delG
NM_000492.3:c.1373del
NM_000492.3:c.1373delG
p.Gly458AspfsX11

Protein change:

G458fs

Links:

dbSNP: rs397508196

NCBI 1000 Genomes Browser:

rs397508196

Molecular consequence:

NM_000492.4:c.1373del - 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
SCV000486665	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jul 19, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000692321	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	no assertion criteria provided	Pathogenic (Oct 28, 2015)	germline	clinical testing
SCV000924259	CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Dec 8, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001362618	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16049310, 9150159 Citation Link,
SCV003002569	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 28, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9150159, 1695717, 7691345, 9725922, 28492532

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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	clinical testing, research
not provided	germline	unknown	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

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

Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations.

Schrijver I, Oitmaa E, Metspalu A, Gardner P.

J Mol Diagn. 2005 Aug;7(3):375-87.

PubMed [citation]

PMID:: 16049310
PMCID:: PMC1867536

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000486665.2

#	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 Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital, SCV000692321.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR2, SCV000924259.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362618.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: CFTR c.1373delG (p.Gly458AspfsX11) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 244091 control chromosomes, predominantly at a frequency of 6.5e-05 within the African or African-American subpopulation in the gnomAD database. c.1373delG has been reported in the literature in an African American individual affected with Cystic Fibrosis (example, Macek_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9150159, 16049310). Multiple clinical diagnostic laboratories and the CFTR2 database have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely 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, SCV003002569.2

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

Description

This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 9150159). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gly458Aspfs*11) 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 also known as 1504delG. ClinVar contains an entry for this variant (Variation ID: 53237). 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

Last Updated: Sep 29, 2024

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