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NM_000492.3(CFTR):c.3718-2477C>T AND not provided

Germline classification:
Pathogenic (10 submissions)
Last evaluated:
Sep 20, 2023
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:
RCV000727872.43

Allele description

NM_000492.3(CFTR):c.3718-2477C>T

Genes:
CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC113633877:CFTR intron 19 DNase I hypersensitive site [Gene]
Variant type:
single nucleotide variant
Cytogenetic location:
7q31.2
Genomic location:
Preferred name:
NM_000492.3(CFTR):c.3718-2477C>T
Other names:
3849+10kbC->T; 3849+10kbC>T
HGVS:
  • NC_000007.14:g.117639961C>T
  • NG_016465.4:g.179178C>T
  • NG_062449.1:g.167C>T
  • NM_000492.4:c.3718-2477C>TMANE SELECT
  • LRG_663t1:c.3718-2477C>T
  • LRG_663:g.179178C>T
  • NC_000007.13:g.117280015C>T
  • c.3717+12191C>T
  • NM_000492.3:c.3718-2477C>T
Nucleotide change:
3849+10KB, C-T
Links:
Cystic Fibrosis Mutation Database: 518; Genetic Testing Registry (GTR): GTR000500233; OMIM: 602421.0062; dbSNP: rs75039782
NCBI 1000 Genomes Browser:
rs75039782
Molecular consequence:
  • NM_000492.4:c.3718-2477C>T - intron variant - [Sequence Ontology: SO:0001627]
Observations:
11

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000603001ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)
Pathogenic
(Sep 20, 2023)
germlineclinical testing

Citation Link,

SCV000855365Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL Classification Definitions 2015)
Pathogenic
(May 8, 2017)
germlineclinical testing

Citation Link,

SCV001134142Quest Diagnostics Nichols Institute San Juan Capistrano
criteria provided, single submitter

(Quest Diagnostics criteria)
Pathogenic
(Aug 11, 2019)
unknownclinical testing

PubMed (26)
[See all records that cite these PMIDs]

SCV001246823CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)
Pathogenic
(Mar 1, 2022)
germlineclinical testing

Citation Link,

SCV001713434Mayo Clinic Laboratories, Mayo Clinic
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jun 18, 2020)
germlineclinical testing

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

Citation Link,

SCV001744069Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus
no assertion criteria provided
Pathogenicgermlineclinical testing

SCV001958004Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Likely pathogenicgermlineclinical testing

SCV002019223Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 7, 2022)
germlineclinical testing

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

SCV002502265AiLife Diagnostics, AiLife Diagnostics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 18, 2022)
germlineclinical testing

PubMed (21)
[See all records that cite these PMIDs]

SCV002817249Athena Diagnostics Inc
criteria provided, single submitter

(Athena Diagnostics Criteria)
Pathogenic
(Jul 3, 2022)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes4not providednot providednot providednot providedclinical testing
not providedgermlineunknown7not providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA.

Sanz DJ, Hollywood JA, Scallan MF, Harrison PT.

PLoS One. 2017;12(9):e0184009. doi: 10.1371/journal.pone.0184009.

PubMed [citation]
PMID:
28863137
PMCID:
PMC5581164

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.

Claustres M, Thèze C, des Georges M, Baux D, Girodon E, Bienvenu T, Audrezet MP, Dugueperoux I, Férec C, Lalau G, Pagin A, Kitzis A, Thoreau V, Gaston V, Bieth E, Malinge MC, Reboul MP, Fergelot P, Lemonnier L, Mekki C, Fanen P, Bergougnoux A, et al.

Hum Mutat. 2017 Oct;38(10):1297-1315. doi: 10.1002/humu.23276. Epub 2017 Jun 28.

PubMed [citation]
PMID:
28603918
See all PubMed Citations (27)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603001.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The CFTR c.3718-2477C>T variant (rs75039782), also known as 3717+12191C>T or 3849+10kbC>T, is reported in the literature in individuals affected with pancreatic sufficient cystic fibrosis (Highsmith 1994, McKone 2003, Ooi 2012, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 7166), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site and activating a nearby cryptic acceptor splice site. Functional assays show that this leads to the abnormal inclusion of intronic sequence, in the form of a new 84bp exon in the CFTR mRNA (Highsmith 1994). The new exon also includes an in-frame termination codon, which is predicted to result in a truncated protein and or absent transcript. Based on available information, this variant is considered to be pathogenic. References: Highsmith WE et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med.1994 331(15):974-80. PMID: 7521937 McKone EF et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003 361(9370):1671-6. PMID: 12767731 Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. PMID: 22658665 Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. PMID: 23974870

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

From Eurofins Ntd Llc (ga), SCV000855365.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134142.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (26)

Description

This variant has been reported in affected individuals with Cystic Fibrosis, congenital bilateral absence of the vas deferens, and CFTR related diseases (PMIDs: 23974870 (2013), 24440181 (2014), 28603918 (2017), 28863137 (2017), and 29261177 (2018)). This variant has also been reported to result in aberrant CFTR splicing, specifically the inclusion of an 84-bp pseudo exon containing a premature stop codon (PMIDs: 24440181 (2014) and 28863137 (2017)). Based on the available information, this variant is classified as pathogenic.

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

From CeGaT Center for Human Genetics Tuebingen, SCV001246823.17

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testingnot provided

Description

CFTR: PM3:Very Strong, PM2, PS3:Moderate

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided3not providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001713434.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided5not providednot providednot provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001744069.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001958004.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV002019223.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002502265.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (21)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Athena Diagnostics Inc, SCV002817249.1

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

Description

This variant has been reported in affected individuals with Cystic Fibrosis, congenital bilateral absence of the vas deferens, and CFTR related diseases (PMIDs: 23974870 (2013), 24440181 (2014), 28603918 (2017), 28863137 (2017), and 29261177 (2018)). This variant has also been reported to result in aberrant CFTR splicing, specifically the inclusion of an 84-bp pseudo exon containing a premature stop codon (PMIDs: 24440181 (2014) and 28863137 (2017)).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

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

Last Updated: Apr 6, 2024