ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3680T>C (p.Leu1227Ser)
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.3680T>C (p.Leu1227Ser)
Variation ID: 53787 Accession: VCV000053787.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117627733 (GRCh38) [ NCBI UCSC ] 7: 117267787 (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 Feb 20, 2024 Feb 11, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3680T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Leu1227Ser missense NC_000007.14:g.117627733T>C NC_000007.13:g.117267787T>C NG_016465.4:g.166950T>C LRG_663:g.166950T>C LRG_663t1:c.3680T>C LRG_663p1:p.Leu1227Ser - Protein change
- L1227S
- Other names
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- Canonical SPDI
- NC_000007.14:117627732:T: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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 | ||
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2021 | RCV000577748.16 | |
CFTR-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Oct 14, 2020 | RCV001831778.9 |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 11, 2022 | RCV001844027.9 |
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
(Nov 21, 2019)
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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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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001167306.1
First in ClinVar: Mar 08, 2020 Last updated: Mar 08, 2020 |
Comment:
This CFTR variant has been previously identified in patients with features of cystic fibrosis. A single submitter in ClinVar classifies the clinical significance of this … (more)
This CFTR variant has been previously identified in patients with features of cystic fibrosis. A single submitter in ClinVar classifies the clinical significance of this variant as uncertain. CFTR c.3680T>C (rs397508593) is present in one individual in a large population dataset4 (gnomAD: 1/249796 total alleles; 0.0004%; no homozygotes). Three bioinformatic tools queried predict that this substitution would probably be damaging, and the leucine residue at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of c.3680T>C to be uncertain at this time. (less)
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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: SCV002027513.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Uncertain significance
(Feb 11, 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: SCV000696982.2
First in ClinVar: Mar 17, 2018 Last updated: Mar 12, 2022 |
Comment:
Variant summary: CFTR c.3680T>C (p.Leu1227Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. … (more)
Variant summary: CFTR c.3680T>C (p.Leu1227Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250388 control chromosomes (gnomAD and publication data). c.3680T>C has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (Jezequel_2000, Grangeia_2007, Havasi_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Nov 28, 2021)
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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: SCV002270317.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This variant is present in population databases (rs397508593, gnomAD 0.0009%). In summary, the available evidence is currently insufficient to determine the role of this variant … (more)
This variant is present in population databases (rs397508593, gnomAD 0.0009%). 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 53787). This missense change has been observed in individuals with congenital bilateral absence of the vas deferens (PMID: 11101688, 17413420). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1227 of the CFTR protein (p.Leu1227Ser). (less)
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Uncertain significance
(Oct 14, 2020)
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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: SCV002075863.1
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: SCV000679445.1
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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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 gene mutations and polymorphism are associated with non-obstructive azoospermia: From case-control study. | Jiang L | Gene | 2017 | PMID: 28456595 |
Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk. | Lim RM | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 25880441 |
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. | Ramalho AS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 25735457 |
Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens. | Havasi V | Fertility and sterility | 2010 | PMID: 20100616 |
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. | Gallati S | Reproductive biomedicine online | 2009 | PMID: 20021716 |
Mutation analysis of the CFTR gene in Slovak cystic fibrosis patients by DHPLC and subsequent sequencing: identification of four novel mutations. | Kolesár P | General physiology and biophysics | 2008 | PMID: 19202204 |
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 |
Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations. | Jézéquel P | Molecular human reproduction | 2000 | PMID: 11101688 |
Text-mined citations for rs397508593 ...
HelpRecord last updated Oct 08, 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.