NM_000492.4(CFTR):c.1766+5G>T AND Cystic fibrosis

Clinical significance:Pathogenic (Last evaluated: Mar 17, 2017)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000046468.11

Allele description [Variation Report for NM_000492.4(CFTR):c.1766+5G>T]

NM_000492.4(CFTR):c.1766+5G>T

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.1766+5G>T
HGVS:
  • NC_000007.14:g.117590444G>T
  • NG_016465.4:g.129661G>T
  • NM_000492.3:c.1766+5G>T
  • NM_000492.4:c.1766+5G>TMANE SELECT
  • LRG_663t1:c.1766+5G>T
  • LRG_663:g.129661G>T
  • NC_000007.13:g.117230498G>T
  • NG_016465.3:g.129661G>T
Links:
dbSNP: rs121908796
NCBI 1000 Genomes Browser:
rs121908796
Molecular consequence:
  • NM_000492.3:c.1766+5G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000492.4:c.1766+5G>T - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

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
SCV000074481Invitaecriteria provided, single submitter
Pathogenic
(Aug 6, 2020)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000677595CFTR2 - CFTR2reviewed by expert panel
Pathogenic
(Mar 17, 2017)
germlineresearch

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

Citation Link,

SCV000696872Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jul 8, 2016)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000712857Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Feb 10, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001167246Johns Hopkins Genomics, Johns Hopkins Universitycriteria provided, single submitter
Pathogenic
(Oct 16, 2019)
germlineclinical testing

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

SCV001169435CFTR-Francecriteria provided, single submitter
Pathogenic
(Jan 29, 2018)
germlinecuration

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

SCV001194057Myriad Women's Health, Inc.criteria provided, single submitter
Likely pathogenic
(Dec 4, 2019)
unknownclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedresearch, curation
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Novel cystic fibrosis mutation (2215insG) in two adolescent Taiwanese siblings.

Wu CL, Shu SG, Zielenski J, Chiang CD, Tsui LC.

J Formos Med Assoc. 2000 Jul;99(7):564-7.

PubMed [citation]
PMID:
10925568

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990
See all PubMed Citations (17)

Details of each submission

From Invitae, SCV000074481.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change falls in intron 13 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs121908796, ExAC 0.02%). This variant has been reported in individuals affected with cystic fibrosis (PMID: 7543385, 12874665), and it has been reported to segregate with cystic fibrosis in affected families (PMID: 7543385, 10925568). This variant is considered to be a common CFTR variant in East Asian populations (PMID: 18456578). It is also known as c.1898+5G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 48685). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and results in a transcript lacking exon 12 (PMID: 23381846, 7543385). For these reasons, this variant has been classified as Pathogenic.

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

From CFTR2 - CFTR2, SCV000677595.1

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696872.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: The CFTR c.1766+5G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 4/5 splicing algorithms predict the weakening or elimination of the splice donor site of exon 13. This prediction is confirmed by cDNA studies performed on RNA isolated from a homozygous patient, showing >95% of transcripts lacking exon 13. This variant was found in 2/119622 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). c.1766+5G>T has been cited in numerous CF patients reported in the literature in both compound heterozygous and homozygous states. Taken together, this variant is classified as Pathogenic.

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

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000712857.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The c.1766+5G>T (NM_000492.3 c.1766+5G>T) variant in CFTR has been reported in 1 homozygous and 3 compound heterozygous Asian individuals with clinical features of cystic fibrosis (Zielenski 1995, Leung 2016, Shen 2016). This variant has be en identified in 0.023% (2/8,562) of East Asian chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121908796). This variant is located in the 3' splice region. Computational tools suggest a possib le impact to splicing consistent with the +5 position being predominantly a G nu cleotide. In summary, the clinical significance of the c.1766+5G>T variant is li kely pathogenic based upon biallelic case observations, suggestive splicing impa ct and low frequency in the general population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001167246.1

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

Description

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

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

From CFTR-France, SCV001169435.1

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

From Myriad Women's Health, Inc., SCV001194057.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

NM_000492.3(CFTR):c.1766+5G>T(aka 1898+5G>T) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 23089694, 8213163, 25580864, 16202790, 7543385, 23381846, 12874665 and 18456578. Classification of NM_000492.3(CFTR):c.1766+5G>T(aka 1898+5G>T) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. 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

Last Updated: Sep 6, 2021

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