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NM_000492.4(CFTR):c.1572C>A (p.Cys524Ter) 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:
RCV000007571.17

Allele description [Variation Report for NM_000492.4(CFTR):c.1572C>A (p.Cys524Ter)]

NM_000492.4(CFTR):c.1572C>A (p.Cys524Ter)

Genes:
CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS1:CFTR antisense RNA 1 [Gene - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7q31.2
Genomic location:
Preferred name:
NM_000492.4(CFTR):c.1572C>A (p.Cys524Ter)
HGVS:
  • NC_000007.14:g.117559643C>A
  • NG_016465.4:g.98860C>A
  • NM_000492.4:c.1572C>AMANE SELECT
  • NP_000483.3:p.Cys524Ter
  • NP_000483.3:p.Cys524Ter
  • LRG_663t1:c.1572C>A
  • LRG_663:g.98860C>A
  • LRG_663p1:p.Cys524Ter
  • NC_000007.13:g.117199697C>A
  • NM_000492.3:c.1572C>A
  • p.Cys524X
Protein change:
C524*; CYS524TER
Links:
OMIM: 602421.0047; dbSNP: rs121908754
NCBI 1000 Genomes Browser:
rs121908754
Molecular consequence:
  • NM_000492.4:c.1572C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000027772OMIM
no assertion criteria provided
Pathogenic
(Apr 1, 1992)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000245954CFTR2 - CFTR2
reviewed by expert panel

(Sosnay PR et al. (Nat Genet 2013))
Pathogenic
(Mar 17, 2017)
germlineresearch

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001193805Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))
Likely pathogenic
(Nov 12, 2019)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001579747Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 19, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004020653Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Jun 14, 2023)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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

Characterization of more than 85% of cystic fibrosis alleles in the Greek population, including five novel mutations.

Tzetis M, Kanavakis E, Antoniadi T, Doudounakis S, Adam G, Kattamis C.

Hum Genet. 1997 Jan;99(1):121-5.

PubMed [citation]
PMID:
9003508
See all PubMed Citations (12)

Details of each submission

From OMIM, SCV000027772.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Using the chemical cleavage mismatch technique for the study of DNA from a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) discovered a nonsense C524X mutation resulting from a C-to-A transversion.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From CFTR2 - CFTR2, SCV000245954.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Myriad Genetics, Inc., SCV001193805.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

NM_000492.3(CFTR):c.1572C>A(C524*) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 9003508 and 1284466. Classification of NM_000492.3(CFTR):c.1572C>A(C524*) 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 observed in an individual with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001579747.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

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 cystic fibrosis (PMID: 1284466, 27717243). ClinVar contains an entry for this variant (Variation ID: 7151). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys524*) in the CFTR gene. It is expected to result in an absent or disrupted protein product.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020653.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: CFTR c.1572C>A (p.Cys524X) 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. The variant allele was found at a frequency of 4e-06 in 250906 control chromosomes. c.1572C>A has been reported in the literature in individuals affected with Cystic Fibrosis (example, Shuber_1997, Zheng_2017, McCague_2019, Chen_2021, Bresnick_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34857524, 34315429, 30888834, 9147636, 27717243). Multiple clinical diagnostic laboratories and a database (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024