VCV000007166.141 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

28 submissions

28 submitters

7 conditions

Practice guidelines

Pathogenic

Mar 2004 by American Colle…

for Cystic fibrosis

Reviewed by expert panel

Pathogenic

Mar 2017 by CFTR2

for Cystic fibrosis

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 7166 Accession: VCV000007166.141

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117639961 (GRCh38) [ NCBI UCSC ] 7: 117280015 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 29, 2015	Dec 7, 2024	Mar 3, 2004

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.3718-2477C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NC_000007.14:g.117639961C>T
NC_000007.13:g.117280015C>T
NG_016465.4:g.179178C>T
NG_062449.1:g.167C>T
LRG_663:g.179178C>T
LRG_663t1:c.3718-2477C>T

... more HGVS ... less HGVS

Protein change

Other names

3849+10kbC->T
3849+10kbC>T
3849+10KB, C-T

Canonical SPDI

NC_000007.14:117639960:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00011

Trans-Omics for Precision Medicine (TOPMed) 0.00012

Links

ClinGen: CA249893 Genetic Testing Registry (GTR): GTR000074114 Genetic Testing Registry (GTR): GTR000500233 Genetic Testing Registry (GTR): GTR000576392 OMIM: 602421.0062 dbSNP: rs75039782 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		-	-	GRCh38 GRCh37	3835	5214
LOC113633877	-	-	-	GRCh38	-	18

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Pathogenic (12)	practice guideline	Mar 3, 2004	RCV000007586.43
not specified	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2017	RCV000507372.13
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Sep 20, 2023	RCV000727872.52
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763159.10
CFTR-related disorder Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2018	RCV001009390.9
Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2021	RCV002257359.9
CFTR-related disorder	Pathogenic (2)	criteria provided, single submitter	Aug 31, 2023	RCV001826438.11

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
pathogenic (Mar 03, 2004)	practice guideline (Guideline for cystic fibrosis carrier screening) Method: curation	Cystic fibrosis (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	American College of Medical Genetics and Genomics (ACMG) Study: The ACMG recommended carrier screening panel Accession: SCV000071406.2 First in ClinVar: Jun 04, 2013 Last updated: Mar 29, 2015	Publications: PubMed (1) PubMed: 11280952 pmc: 3110945 pmc: 3110945 Comment: Converted during submission to Pathogenic.
Pathogenic (Mar 17, 2017)	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013)) Method: research	Cystic fibrosis Affected status: yes Allele origin: germline	CFTR2 Study: CFTR2 Accession: SCV000071573.4 First in ClinVar: Oct 18, 2013 Last updated: Dec 26, 2017	Other databases https://cftr2.org https://cftr2.org
Pathogenic (May 08, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000855365.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR Number of individuals with the variant: 2 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Jan 29, 2018)	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	cystic fibrosis CFTR-related disorders Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169243.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Comment: when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Pathogenic (Nov 12, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193976.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (1) PubMed: 23974870 Comment: NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) is classified as pathogenic in the context of cystic fibrosis and is associated with non-classic disease. Sources cited for classification include the following: … (more) NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) is classified as pathogenic in the context of cystic fibrosis and is associated with non-classic disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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. (less)
Pathogenic (Aug 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CFTR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004114477.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The CFTR c.3718-2477C>T variant is predicted to interfere with splicing. This variant is also referred to as 3849+10kbC>T or c.3717+12191C>T. This variant has previously been … (more) The CFTR c.3718-2477C>T variant is predicted to interfere with splicing. This variant is also referred to as 3849+10kbC>T or c.3717+12191C>T. This variant has previously been reported to be causative in multiple cystic fibrosis patients with a mild phenotype (Highsmith et al. 1994. PubMed ID: 7521937; McKone et al. 2003. PubMed ID: 12767731; Duguépéroux et al. 2005. PubMed ID: 15738290; Sosnay et al. 2013. PubMed ID: 23974870; cftr2.org) and is included in the American College Medical Genetics (ACMG) panel of CF variants (Watson et al. 2004. PubMed ID: 15371902; Deignan JL et al. 2023. PubMed ID: 37310422). We classify this variant as pathogenic. (less)
Pathogenic (Sep 20, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603001.6 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: 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 … (more) 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 (less)
Pathogenic (Jan 28, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000074964.14 First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 28492532‚ 15371902‚ 23974870‚ 26631874‚ 7521937 Comment: This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. … (more) This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs75039782, gnomAD 0.3%). This variant has been observed in individual(s) with cystic fibrosis (CF) and is included in the American College of Medical Genetics panel of CF variants (PMID: 15371902, 23974870, 26631874). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 3849+10kbC>T in intron 19. ClinVar contains an entry for this variant (Variation ID: 7166). Studies have shown that this variant results in inclusion of a pseudo-exon and introduces a premature termination codon (PMID: 7521937). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848808.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The c.3718-2477C>T variant in CFTR (also known as 3849+10kbC>T) has been reported, in the homozygous and compound heterozygous state, in numerous individuals with cystic fibrosis … (more) The c.3718-2477C>T variant in CFTR (also known as 3849+10kbC>T) has been reported, in the homozygous and compound heterozygous state, in numerous individuals with cystic fibrosis with and without pancreatic insufficiency (selected publications: Abeliovich 1992 PMID: 1384328, Highsmith 1994 PMID: 7521937, Liang 1998 PMID: 9719631, Watson 2004 PMID: 15371902, de Gracia 2005 PMID: 15994263, Duguépéroux 2005 PMID: 15738290, Ooi 2011 PMID: 20923678). It has also been identified in 0.2% (6/3470) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This deep intronic variant was classified as Pathogenic on Mar 17 2017 by the ClinGen-approved CFTR2 expert panel (also pathogenic per practice guideline) (Variation ID 7166). In vitro functional studies have shown that this variant creates a cryptic splice site that causes the creation of a new exon containing an in-frame premature stop codon, the resulting mRNA is predicted to undergo nonsense-mediated decay (Highsmith 1994 PMID: 7521937). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM2_supporting, PM3_Very Strong, PS3. (less)
Pathogenic (Feb 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713434.2 First in ClinVar: Jun 15, 2021 Last updated: Jun 09, 2024	Other databases https://cftr2.org/ https://cftr2.org/ Number of individuals with the variant: 10
Pathogenic (Oct 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cystic fibrosis Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV005420806.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024	Comment: PS3,PM3(very strong),PM2
Pathogenic (Dec 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: unknown	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University Accession: SCV000891678.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018	Geographic origin: Middle East
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893746.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Dec 13, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917222.2 First in ClinVar: Jun 03, 2019 Last updated: Jun 24, 2023	Publications: PubMed (5) PubMed: 7521937‚ 8533846‚ 15738290‚ 23974870‚ 26014425 Comment: Variant summary: The CFTR c.3718-2477C>T variant involves the alteration of a non-conserved deep intronic nucleotide. One in silico tool predicts a disease-causing outcome for this … (more) Variant summary: The CFTR c.3718-2477C>T variant involves the alteration of a non-conserved deep intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict a significant impact on splicing. Functional analysis confirms that this variant is associated with an abnormally spliced product (Highsmith_1994). This variant was found in 2/30924 control chromosomes (gnomAD) at a frequency of 0.0000647, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in multiple CF patients with a mild phenotype, including 3 homozygotes (Duguproux_2005, Gilbert_1995) and was included in the ACMG CFTR list (Watson_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Mar 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502265.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (20) PubMed: 7521937‚ 29261177‚ 31036917‚ 18456578‚ 10351951‚ 9799593‚ 24440181‚ 9272738‚ 34426522‚ 22975760‚ 9719631‚ 12767731‚ 7526685‚ 20923678‚ 22658665‚ 11484207‚ 32429104‚ 23974870‚ 7533604‚ 19823873 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529716.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The CFTR c.3718-2477C>T variant has been reported as homozygous and compound heterozygous in numerous individuals with cystic fibrosis (PMID: 1384328, 7521937, 9719631, 15371902, 15994263, 15738290, … (more) The CFTR c.3718-2477C>T variant has been reported as homozygous and compound heterozygous in numerous individuals with cystic fibrosis (PMID: 1384328, 7521937, 9719631, 15371902, 15994263, 15738290, 20923678). It is also known as 3849+10kb C>T in the literature. The variant has been reported in patients with and without pancreatic insufficiency and to cause a variable phenotype (PMID: 9719631, 15994263, 15738290). Experimental studies have shown that this variant creates a cryptic splice site that causes the creation of a new exon containing an in-frame premature stop codon (PMID: 7521937). It was observed in 18/152004 chromosomes in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 7166). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (7) PubMed: 1384328‚ 7521937‚ 9719631‚ 15371902‚ 15994263‚ 15738290‚ 20923678
Pathogenic (Jun 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002568229.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Comment: PS3, PM2, PM3_Very Strong, PP3
Pathogenic (Sep 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cystic fibrosis Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002573860.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: This variant was identified in 10 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a … (more) This variant was identified in 10 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3, PM2_SUP, PM3_VSTR, PM4, PP4 (less) Number of individuals with the variant: 10
Pathogenic (Nov 05, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: unknown	Mendelics Accession: SCV000886228.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Jul 03, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV002817249.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: 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), … (more) 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. (less)
Pathogenic (Aug 11, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001134142.4 First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2024	Publications: PubMed (25) PubMed: 29261177‚ 28863137‚ 28603918‚ 10351951‚ 11484207‚ 12767731‚ 18456578‚ 19823873‚ 20923678‚ 22658665‚ 22975760‚ 31036917‚ 32429104‚ 34426522‚ 7521937‚ 7533604‚ 9272738‚ 9719631‚ 9799593‚ 24440181‚ 23974870‚ 7526685‚ 8533846‚ 15738290‚ 15371902 Comment: 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), … (more) 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. (less)
Pathogenic (Mar 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019223.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246823.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: CFTR: PM3:Very Strong, PM2, PS3:Moderate Number of individuals with the variant: 3
Pathogenic (Jul 03, 1993)	no assertion criteria provided Method: literature only	CYSTIC FIBROSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027787.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017	Publications: PubMed (2) PubMed: 1384328‚ 8100293 Highsmith, W. E., Jr. Personal (more...) Highsmith, W. E., Jr. Personal Communication. 1991. Chapel Hill, N.C. Highsmith, W. E., Burch, L. H., (more...) Highsmith, W. E., Burch, L. H., Boat, T. F., Boucher, R. C., Silverman, L. M., Knowles, M. R. Identification of a homozygous point mutation in intron 19 in an inbred CF patient with mild disease and normal sweat chloride: creation of an alternative splice site resulting in base-sequence insertion in CFTR coding region between exons 19 and 20. (Abstract) Pediat. Pulmonol. Suppl. 6: 22A, 1991. Comment on evidence: Abeliovich et al. (1992) found that among 94 Ashkenazi Jewish patients with cystic fibrosis (CF; 219700) in Israel, 5 mutations accounted for 97% of mutant … (more) Abeliovich et al. (1992) found that among 94 Ashkenazi Jewish patients with cystic fibrosis (CF; 219700) in Israel, 5 mutations accounted for 97% of mutant CFTR alleles. Four of these were delF508 (602421.0001), G542X (602421.0009), W1282X (602421.0022), and N1303K (602421.0032). The fifth, which accounted for 4% of alleles, was an unusual mutation found by Highsmith (1991). Referred to as 3849+10kbC-T, it was detected by cleavage of a PCR product by HphI. Highsmith et al. (1991) detected the 3849+10kbC-T mutation in a 19-year-old Pakistani woman with mild manifestations of CF and normal sweat chloride values. To explain the milder course of the disease in patients with this mutation, Highsmith et al. (1991) hypothesized that the C-to-T base substitution created an alternative splice site, which resulted in insertion of 84 basepairs into the CFTR coding region. This change may cause synthesis of a protein with normal CFTR function together with a nonfunctional protein. Alternatively, this mutation might lead to production of a protein that is only partly functional and causes milder disease. In Israel, Augarten et al. (1993) investigated 15 patients with CF and this mutation, all Ashkenazi Jews. Their clinical features were compared with those of CF patients with mutations known to be associated with severe disease. Patients with the 3849+10kbC-T mutation were older, had been diagnosed as having CF at a more advanced age, and were in a better nutritional state. Sweat chloride values were normal in 5 of the 15 patients; 4 of these patients and 6 others had normal pancreatic function. However, age-adjusted pulmonary function did not differ between these patients and those with mutations known to cause severe disease. None of the patients with the 3849+10kbC-T mutation had had meconium ileus and none had liver disease or diabetes mellitus. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958004.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744069.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (Jul 26, 2017)	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002075873.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
not provided (-)	no classification provided Method: literature only	Cystic fibrosis Affected status: unknown Allele origin: unknown	GeneReviews Accession: SCV001622805.2 First in ClinVar: May 23, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301428‚ 15371902 BookShelf: NBK1250 BookShelf: NBK1250
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Highsmith, W. E., Burch, L. H., Boat, T. F., Boucher, R. C., Silverman, L. M., Knowles, M. R. Identification of a homozygous point mutation in intron 19 in an inbred CF patient with mild disease and normal sweat chloride: creation of an alternative splice site resulting in base-sequence insertion in CFTR coding region between exons 19 and 20. (Abstract) Pediat. Pulmonol. Suppl. 6: 22A, 1991.

Comment:

NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) is classified as pathogenic in the context of cystic fibrosis and is associated with non-classic disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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.

Comment:

The CFTR c.3718-2477C>T variant is predicted to interfere with splicing. This variant is also referred to as 3849+10kbC>T or c.3717+12191C>T. This variant has previously been reported to be causative in multiple cystic fibrosis patients with a mild phenotype (Highsmith et al. 1994. PubMed ID: 7521937; McKone et al. 2003. PubMed ID: 12767731; Duguépéroux et al. 2005. PubMed ID: 15738290; Sosnay et al. 2013. PubMed ID: 23974870; cftr2.org) and is included in the American College Medical Genetics (ACMG) panel of CF variants (Watson et al. 2004. PubMed ID: 15371902; Deignan JL et al. 2023. PubMed ID: 37310422). We classify this variant as pathogenic.

Comment:

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

Comment:

This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs75039782, gnomAD 0.3%). This variant has been observed in individual(s) with cystic fibrosis (CF) and is included in the American College of Medical Genetics panel of CF variants (PMID: 15371902, 23974870, 26631874). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 3849+10kbC>T in intron 19. ClinVar contains an entry for this variant (Variation ID: 7166). Studies have shown that this variant results in inclusion of a pseudo-exon and introduces a premature termination codon (PMID: 7521937). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.3718-2477C>T variant in CFTR (also known as 3849+10kbC>T) has been reported, in the homozygous and compound heterozygous state, in numerous individuals with cystic fibrosis with and without pancreatic insufficiency (selected publications: Abeliovich 1992 PMID: 1384328, Highsmith 1994 PMID: 7521937, Liang 1998 PMID: 9719631, Watson 2004 PMID: 15371902, de Gracia 2005 PMID: 15994263, Duguépéroux 2005 PMID: 15738290, Ooi 2011 PMID: 20923678). It has also been identified in 0.2% (6/3470) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This deep intronic variant was classified as Pathogenic on Mar 17 2017 by the ClinGen-approved CFTR2 expert panel (also pathogenic per practice guideline) (Variation ID 7166). In vitro functional studies have shown that this variant creates a cryptic splice site that causes the creation of a new exon containing an in-frame premature stop codon, the resulting mRNA is predicted to undergo nonsense-mediated decay (Highsmith 1994 PMID: 7521937). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM2_supporting, PM3_Very Strong, PS3.

Comment:

Variant summary: The CFTR c.3718-2477C>T variant involves the alteration of a non-conserved deep intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict a significant impact on splicing. Functional analysis confirms that this variant is associated with an abnormally spliced product (Highsmith_1994). This variant was found in 2/30924 control chromosomes (gnomAD) at a frequency of 0.0000647, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in multiple CF patients with a mild phenotype, including 3 homozygotes (Duguproux_2005, Gilbert_1995) and was included in the ACMG CFTR list (Watson_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

This variant was identified in 10 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3, PM2_SUP, PM3_VSTR, PM4, PP4

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.	Petrova NV	Genes	2020	PMID: 32429104
Sequencing as a first-line methodology for cystic fibrosis carrier screening.	Beauchamp KA	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31036917
Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests.	Archibald AD	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29261177
Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA.	Sanz DJ	PloS one	2017	PMID: 28863137
CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.	Claustres M	Human mutation	2017	PMID: 28603918
Cystic Fibrosis: A Review of Associated Phenotypes, Use of Molecular Diagnostic Approaches, Genetic Characteristics, Progress, and Dilemmas.	Brennan ML	The Journal of molecular diagnostics : JMD	2016	PMID: 26631874
The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus.	Girardet A	European journal of human genetics : EJHG	2016	PMID: 26014425
The relative frequency of CFTR mutation classes in European patients with cystic fibrosis.	De Boeck K	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2014	PMID: 24440181
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.	Lazarin GA	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22975760
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis.	Ooi CY	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2012	PMID: 22658665
Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.	Ooi CY	Gastroenterology	2011	PMID: 20923678
CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening.	Chávez-Saldaña M	Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion	2010	PMID: 21416780
Transposable elements in disease-associated cryptic exons.	Vorechovsky I	Human genetics	2010	PMID: 19823873
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.	Castellani C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18456578
Genotype-phenotype correlation for pulmonary function in cystic fibrosis.	de Gracia J	Thorax	2005	PMID: 15994263
The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype.	Duguépéroux I	The European respiratory journal	2005	PMID: 15738290
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.	Watson MS	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15371902
Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study.	McKone EF	Lancet (London, England)	2003	PMID: 12767731
XV-2c/KM-19 haplotype analysis of cystic fibrosis mutations in Mexican patients.	Orozco L	American journal of medical genetics	2001	PMID: 11484207
Variable levels of normal RNA in different fetal organs carrying a cystic fibrosis transmembrane conductance regulator splicing mutation.	Chiba-Falek O	American journal of respiratory and critical care medicine	1999	PMID: 10351951
The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C-->T mutation.	Chiba-Falek O	Genomics	1998	PMID: 9799593
3849 + 10 kb C --> T splicing mutation in Hispanic CF patients.	Liang MH	Molecular genetics and metabolism	1998	PMID: 9719631
CFTR gene mutations in adults with disseminated bronchiectasis.	Girodon E	European journal of human genetics : EJHG	1997	PMID: 9272738
Clinical spectrum in homozygotes and compound heterozygotes inheriting cystic fibrosis mutation 3849 + 10kbC > T: significance for geneticists.	Gilbert F	American journal of medical genetics	1995	PMID: 8533846
Normal sweat chloride values do not exclude the diagnosis of cystic fibrosis.	Stewart B	American journal of respiratory and critical care medicine	1995	PMID: 7533604
Independent origins of cystic fibrosis mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T provide evidence of mutation recurrence in the CFTR gene.	Morral N	American journal of human genetics	1994	PMID: 7526685
A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations.	Highsmith WE	The New England journal of medicine	1994	PMID: 7521937
Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849 + 10 kb C-->T mutation.	Augarten A	Lancet (London, England)	1993	PMID: 8100293
Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population.	Abeliovich D	American journal of human genetics	1992	PMID: 1384328
Highsmith, W. E., Burch, L. H., Boat, T. F., Boucher, R. C., Silverman, L. M., Knowles, M. R. Identification of a homozygous point mutation in intron 19 in an inbred CF patient with mild disease and normal sweat chloride: creation of an alternative splice site resulting in base-sequence insertion in CFTR coding region between exons 19 and 20. (Abstract) Pediat. Pulmonol. Suppl. 6: 22A, 1991.	-	-	-	-
Highsmith, W. E., Jr. Personal Communication. 1991. Chapel Hill, N.C.	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
https://cftr2.org	-	-	-	-
https://cftr2.org/	-	-	-	-
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Text-mined citations for rs75039782 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 07, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

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Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs75039782 ...