ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3322G>C (p.Val1108Leu)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3322G>C (p.Val1108Leu)
Variation ID: 53719 Accession: VCV000053719.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117611763 (GRCh38) [ NCBI UCSC ] 7: 117251817 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 25, 2018 May 1, 2024 Feb 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3322G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Val1108Leu missense NC_000007.14:g.117611763G>C NC_000007.13:g.117251817G>C NG_016465.4:g.150980G>C NG_056128.2:g.4817G>C LRG_663:g.150980G>C LRG_663t1:c.3322G>C LRG_663p1:p.Val1108Leu - Protein change
- V1108L
- Other names
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- Canonical SPDI
- NC_000007.14:117611762:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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CFTR | - | - |
GRCh38 GRCh37 |
3821 | 5195 | |
LOC111674472 | - | - | - | GRCh38 | - | 400 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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CFTR-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Sep 4, 2018 | RCV001826663.9 |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 18, 2020 | RCV001811325.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 16, 2022 | RCV002509190.8 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2024 | RCV000577410.16 |
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
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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
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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. |
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Uncertain significance
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002027494.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Uncertain significance
(Dec 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819604.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: CFTR c.3322G>C (p.Val1108Leu) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded … (more)
Variant summary: CFTR c.3322G>C (p.Val1108Leu) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250936 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3322G>C has been reported in the literature as a non-informative genotype (second allele not-specified) or in cis with a pathogenic CFTR allele (see detailed below) in individuals with features of CBAVD, chronic bronchitis (COPDGene study cohort) (example, Grangeia_2007, Steiner_2011, Pagin_2016, Safareli_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At-least one co-occurrence in cis with another pathogenic variant(s) have been reported (CFTR c.3454G>C, p.Asp1152His) reportedly in trans with the 5T allele in an individual with CBAVD, providing supporting evidence for a benign role (Steiner_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Feb 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002611650.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.V1108L variant (also known as c.3322G>C), located in coding exon 20 of the CFTR gene, results from a G to C substitution at nucleotide … (more)
The p.V1108L variant (also known as c.3322G>C), located in coding exon 20 of the CFTR gene, results from a G to C substitution at nucleotide position 3322. The valine at codon 1108 is replaced by leucine, an amino acid with highly similar properties. This alteration was reported in a 37 year old with CBAVD and no other clinical manifestations of cystic fibrosis; he was also heterozygous for the 11-5T variant, phase not reported (Grangeia A, Genet. Med. 2007 Mar; 9(3):163-72). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Aug 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001472857.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The CFTR c.3322G>C; p.Val1108Leu variant (rs397508542) is reported in the literature in an individual affected with congenital absence of the vas deferens who also carried … (more)
The CFTR c.3322G>C; p.Val1108Leu variant (rs397508542) is reported in the literature in an individual affected with congenital absence of the vas deferens who also carried a pathogenic-mild CFTR variant (Grangeia 2007). This variant is reported in ClinVar (Variation ID: 53719), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 1108 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Val1108Leu variant is uncertain at this time. References: Grangeia A et al. Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. Genet Med. 2007;9(3):163-172. (less)
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Uncertain significance
(Jun 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001556595.2
First in ClinVar: Apr 13, 2021 Last updated: Mar 26, 2023 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1108 of the CFTR protein (p.Val1108Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1108 of the CFTR protein (p.Val1108Leu). This variant is present in population databases (rs397508542, gnomAD 0.004%). This missense change has been observed in individual(s) with a CFTR-related disorder and congenital absence of the vas deferens (PMID: 17413420, 28603918). ClinVar contains an entry for this variant (Variation ID: 53719). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Sep 04, 2018)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083635.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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CFTR-related disorders
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000679051.1
First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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C FTR variants are associated with chronic bronchitis in smokers. | Saferali A | The European respiratory journal | 2022 | PMID: 34996830 |
Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling. | de Souza DAS | Andrology | 2018 | PMID: 29216686 |
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 |
Applicability and Efficiency of NGS in Routine Diagnosis: In-Depth Performance Analysis of a Complete Workflow for CFTR Mutation Analysis. | Pagin A | PloS one | 2016 | PMID: 26900683 |
Novel mutations and polymorphisms in the CFTR gene associated with three subtypes of congenital absence of vas deferens. | Yang X | Fertility and sterility | 2015 | PMID: 26277102 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. | Grangeia A | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17413420 |
Text-mined citations for rs397508542 ...
HelpRecord last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.