NM_000492.4(CFTR):c.1573del (p.Gln525fs) AND Cystic fibrosis

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 13, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001386721.8

Allele description [Variation Report for NM_000492.4(CFTR):c.1573del (p.Gln525fs)]

NM_000492.4(CFTR):c.1573del (p.Gln525fs)

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.1573del (p.Gln525fs)

HGVS:

NC_000007.14:g.117559644del
NG_016465.4:g.98861del
NM_000492.4:c.1573delMANE SELECT
NP_000483.3:p.Gln525fs
LRG_663t1:c.1573del
LRG_663:g.98861del
NC_000007.13:g.117199697del
NC_000007.13:g.117199698del
NM_000492.3:c.1573delC
NM_000492.4:c.1573delCMANE SELECT

Protein change:

Q525fs

Links:

dbSNP: rs774433839

NCBI 1000 Genomes Browser:

rs774433839

Molecular consequence:

NM_000492.4:c.1573del - 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
SCV001587067	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 24, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 1695717, 7691345, 9725922, 28492532
SCV003863074	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 14, 2023)	germline	clinical testing	Citation Link,
SCV005204267	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 13, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001587067

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 24, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003863074

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 14, 2023)

germline

clinical testing

Citation Link,

SCV005204267

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 13, 2024)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.

Yang Y, Devor DC, Engelhardt JF, Ernst SA, Strong TV, Collins FS, Cohn JA, Frizzell RA, Wilson JM.

Hum Mol Genet. 1993 Aug;2(8):1253-61.

PubMed [citation]

PMID:: 7691345

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001587067.4

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

Description

This sequence change creates a premature translational stop signal (p.Gln525Asnfs*2) in the CFTR gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs774433839, ExAC 0.009%). This variant has not been reported in the literature in individuals with CFTR-related conditions. 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.

#	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, SCV003863074.2

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

Description

The c.1573delC pathogenic mutation, located in coding exon 11 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 1573, causing a translational frameshift with a predicted alternate stop codon (p.Q525Nfs*2). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005204267.1

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

Description

Variant summary: CFTR c.1573delC (p.Gln525AsnfsX2) 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. The variant allele was found at a frequency of 4e-06 in 250956 control chromosomes. To our knowledge, no occurrence of c.1573delC in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1073653). 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

Last Updated: Sep 29, 2024

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