ClinVar Genomic variation as it relates to human health
NM_006005.3(WFS1):c.2119G>A (p.Val707Ile)
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_006005.3(WFS1):c.2119G>A (p.Val707Ile)
Variation ID: 215367 Accession: VCV000215367.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.1 4: 6301914 (GRCh38) [ NCBI UCSC ] 4: 6303641 (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 May 29, 2016 Sep 16, 2024 Feb 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006005.3:c.2119G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005996.2:p.Val707Ile missense NM_001145853.1:c.2119G>A NP_001139325.1:p.Val707Ile missense NC_000004.12:g.6301914G>A NC_000004.11:g.6303641G>A NG_011700.1:g.37065G>A LRG_1417:g.37065G>A LRG_1417t1:c.2119G>A LRG_1417p1:p.Val707Ile - Protein change
- V707I
- Other names
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- Canonical SPDI
- NC_000004.12:6301913:G:A
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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) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00013
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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
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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WFS1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1742 | 1843 |
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
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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 (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001157674.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001157675.4 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 29, 2024 | RCV001853208.6 | |
Uncertain risk allele (1) |
criteria provided, single submitter
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- | RCV003128189.1 |
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
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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
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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WFS1-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001319271.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 6
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001319270.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain risk allele
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Wolfram syndrome 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV003804224.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
Comment:
Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However … (more)
Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs71524377 in Wolfram's syndrome yet. (less)
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Uncertain significance
(Jan 12, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002160330.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 707 of the WFS1 protein (p.Val707Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 707 of the WFS1 protein (p.Val707Ile). This variant is present in population databases (rs71524377, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 215367). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 95%. 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
(Jan 06, 2023)
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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: SCV004564263.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The WFS1 c.2119G>A; p.Val707Ile variant (rs71524377) is reported in cis to a frameshift WFS1 variant in several individuals with Wolfram syndrome or non-syndromic diabetes (Zalloua … (more)
The WFS1 c.2119G>A; p.Val707Ile variant (rs71524377) is reported in cis to a frameshift WFS1 variant in several individuals with Wolfram syndrome or non-syndromic diabetes (Zalloua 2008). This variant is also reported in ClinVar (Variation ID: 215367). It is observed in the general population with an overall allele frequency of 0.004% (11/281244 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.579). Due to limited information the clinical significance of this variant is uncertain at this time. References: Zalloua PA et al. WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon. Hum Mol Genet. 2008 Dec 15;17(24):4012-21. PMID: 18806274. (less)
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Uncertain significance
(Feb 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000252496.12
First in ClinVar: Oct 11, 2015 Last updated: Sep 16, 2024 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31850070, 20738327, 23429432, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31850070, 20738327, 23429432, 30245029, 18806274) (less)
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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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WFS1 Spectrum Disorder. | Adam MP | - | 2022 | PMID: 20301750 |
A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1. | Gong Y | BMC endocrine disorders | 2021 | PMID: 33879153 |
Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. | de Heredia ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 23429432 |
Wolfram syndrome and WFS1 gene. | Rigoli L | Clinical genetics | 2011 | PMID: 20738327 |
WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon. | Zalloua PA | Human molecular genetics | 2008 | PMID: 18806274 |
Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program. | Florez JC | Diabetologia | 2008 | PMID: 18060660 |
Common variants in WFS1 confer risk of type 2 diabetes. | Sandhu MS | Nature genetics | 2007 | PMID: 17603484 |
Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. | Cryns K | Human mutation | 2003 | PMID: 12955714 |
Text-mined citations for rs71524377 ...
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.