VCV000632759.8 - ClinVar

NM_000492.4(CFTR):c.3717+1G>A

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

4 out of 5 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.3717+1G>A

Variation ID: 632759 Accession: VCV000632759.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117627771 (GRCh38) [ NCBI UCSC ] 7: 117267825 (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	Jun 3, 2019	Feb 25, 2025	Sep 5, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.3717+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000007.14:g.117627771G>A
NC_000007.13:g.117267825G>A
NG_016465.4:g.166988G>A
LRG_663:g.166988G>A
LRG_663t1:c.3717+1G>A

... more HGVS ... less HGVS

Protein change

Other names

3849+1G->A

Canonical SPDI

NC_000007.14:117627770:G:A

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) 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA4451520 dbSNP: rs750558115 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		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	4093	5563

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.
not specified	Pathogenic (1)	criteria provided, single submitter	Apr 16, 2018	RCV000780151.1
Cystic fibrosis	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 5, 2022	RCV001009420.6
CFTR-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 17, 2017	RCV001830671.1

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 (Apr 16, 2018) C Contributing to aggregate classification	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: SCV000917198.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (3) PubMed: 17331079‚ 7509231‚ 12938099 Comment: Variant summary: CFTR c.3717+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: CFTR c.3717+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-06 in 241448 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (8.3e-06 vs 1.30e-02), allowing no conclusion about variant significance. c.3717+1G>A has been reported in the literature in individuals affected with Cystic Fibrosis (Greil_1993, Keyeux_2003, Nahida_2011, Alonso_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Pathogenic (Jan 29, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	cystic fibrosis Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169358.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918

Likely pathogenic (Sep 05, 2022) C Contributing to aggregate classification	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: SCV002574082.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: This variant was identified in 2 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 2 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: PVS1_STR, PM2_SUP, PM3 (less) Number of individuals with the variant: 2

Pathogenic (Apr 12, 2022) C Contributing to aggregate classification	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: SCV003440164.3 First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025	Publications: PubMed (8) PubMed: 7509231‚ 12938099‚ 17331079‚ 21449922‚ 16199547‚ 1695717‚ 7691345‚ 9725922 Comment: ClinVar contains an entry for this variant (Variation ID: 632759). This variant is also known as 3849+1G>A. Disruption of this splice site has been observed … (more) ClinVar contains an entry for this variant (Variation ID: 632759). This variant is also known as 3849+1G>A. Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 7509231, 12938099, 17331079, 21449922). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs750558115, gnomAD 0.007%). This sequence change affects a donor splice site in intron 22 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Mar 17, 2017) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002075870.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

Variant summary: CFTR c.3717+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-06 in 241448 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (8.3e-06 vs 1.30e-02), allowing no conclusion about variant significance. c.3717+1G>A has been reported in the literature in individuals affected with Cystic Fibrosis (Greil_1993, Keyeux_2003, Nahida_2011, Alonso_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This variant was identified in 2 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: PVS1_STR, PM2_SUP, PM3

Comment:

ClinVar contains an entry for this variant (Variation ID: 632759). This variant is also known as 3849+1G>A. Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 7509231, 12938099, 17331079, 21449922). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs750558115, gnomAD 0.007%). This sequence change affects a donor splice site in intron 22 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Pseudo-Bartter's syndrome revealing cystic fibrosis in an infant caused by 3849 + 1G>A and 4382delA compound heterozygosity.	Nahida el-R	Acta paediatrica (Oslo, Norway : 1992)	2011	PMID: 21449922
Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.	Alonso MJ	Annals of human genetics	2007	PMID: 17331079
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
CFTR mutations in patients from Colombia: implications for local and regional molecular diagnosis programs.	Keyeux G	Human mutation	2003	PMID: 12938099
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.	Cohn JA	The New England journal of medicine	1998	PMID: 9725922
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.	Yang Y	Human molecular genetics	1993	PMID: 7691345
Identification of a new splice site mutation (3849 + 1G-->A) in the intron 19 of the CFTR gene.	Greil I	Human molecular genetics	1993	PMID: 7509231
A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.	Cutting GR	Nature	1990	PMID: 1695717

Text-mined citations for rs750558115 ...

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 May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.3717+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs750558115 ...