ClinVar Genomic variation as it relates to human health
NM_006005.3(WFS1):c.2171C>T (p.Pro724Leu)
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.
Pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006005.3(WFS1):c.2171C>T (p.Pro724Leu)
Variation ID: 4509 Accession: VCV000004509.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.1 4: 6301966 (GRCh38) [ NCBI UCSC ] 4: 6303693 (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 Jul 30, 2015 Mar 10, 2024 Jul 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006005.3:c.2171C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005996.2:p.Pro724Leu missense NM_001145853.1:c.2171C>T NP_001139325.1:p.Pro724Leu missense NC_000004.12:g.6301966C>T NC_000004.11:g.6303693C>T NG_011700.1:g.37117C>T LRG_1417:g.37117C>T LRG_1417t1:c.2171C>T LRG_1417p1:p.Pro724Leu O76024:p.Pro724Leu - Protein change
- P724L
- Other names
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- Canonical SPDI
- NC_000004.12:6301965:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00007
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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WFS1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1730 | 1831 |
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
Help
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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Pathogenic (1) |
no assertion criteria provided
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Oct 1, 1998 | RCV000004767.5 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jul 11, 2023 | RCV000756934.18 |
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
(May 03, 2018)
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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: SCV000884924.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The WFS1 c.2171C>T; p.Pro724Leu variant (rs28937890) has been previously observed as a homozygote in a pair of siblings from a consanguineous Japanese family with a … (more)
The WFS1 c.2171C>T; p.Pro724Leu variant (rs28937890) has been previously observed as a homozygote in a pair of siblings from a consanguineous Japanese family with a Wolfram syndrome phenotype (minimally, juvenile-onset diabetes mellitus and optic atrophy; Inoue 1998). Numerous functional studies have demonstrated that this variant effects WFS1 protein stability (Hofmann 2006), localization (Fonseca 2005), increased tendency for aggregation (De Franco 2017), and interactions with ATF6 (Fonseca 2010). This variant is found in the general population with an overall allele frequency of 0.003% (8/243,604 alleles) in the Genome Aggregation Database. Based on the available information, the clinical significance of this variant cannot be determined with certainty. De Franco E et al. Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. Diabetes. 2017 Jul;66(7):2044-2053. Fonseca SG et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem. 2005 Nov 25;280(47):39609-15 Fonseca SG et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010 Mar;120(3):744-55. Hofmann S and Bauer M. Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin. FEBS Lett. 2006 Jul 10;580(16):4000-4. Inoue H et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998 Oct;20(2):143-8. (less)
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Pathogenic
(Sep 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001477211.2
First in ClinVar: Jan 26, 2021 Last updated: Sep 19, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been associated with autosomal recessive Wolfram Syndrome (PMID: … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been associated with autosomal recessive Wolfram Syndrome (PMID: 9771706, 24890733) and autosomal recessive Optic Atrophy (PMID: 27395765). This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant abrogates the ability of WFS1 to negatively regulate ATF6-alpha, a transcription factor that is responsible for upregulating stress signaling targets, thereby causing ER-stress mediated apoptosis in pancreatic beta-cells (PMID: 20160352). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(Jul 11, 2023)
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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: SCV004014203.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
Published functional studies demonstrate a damaging effect resulting in abnormal ERSE reporter activity in pancreatic beta-cells (Fonseca et al., 2005; De Franco et al., 2017); … (more)
Published functional studies demonstrate a damaging effect resulting in abnormal ERSE reporter activity in pancreatic beta-cells (Fonseca et al., 2005; De Franco et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22983116, 20160352, 11709537, 11317350, 12955714, 24424032, 26435059, 16806192, 21454619, 28468959, 24227685, 27434582, 11244483, 34406036, 34848728, 37185285, 12618560, 24890733, 30245029, 9771706, 33663443, 27395765, 34404380, 36208030, 25211237, 16195229) (less)
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Pathogenic
(Oct 27, 2021)
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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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Invitae
Accession: SCV002228116.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects WFS1 function (PMID: 16195229, 16806192). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects WFS1 function (PMID: 16195229, 16806192). 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 expected to disrupt WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 4509). This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 9771706, 24890733). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28937890, gnomAD 0.03%). This sequence change replaces proline, a(n) neutral and non-polar amino acid, with leucine, a(n) neutral and non-polar amino acid, at codon 724 of the WFS1 protein (p.Pro724Leu). (less)
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Pathogenic
(Oct 01, 1998)
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no assertion criteria provided
Method: literature only
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WOLFRAM SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024943.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In a Japanese family segregating Wolfram syndrome (WFS1; 222300), Inoue et al. (1998) demonstrated that affected members were homozygous for a 2341C-T transition resulting in … (more)
In a Japanese family segregating Wolfram syndrome (WFS1; 222300), Inoue et al. (1998) demonstrated that affected members were homozygous for a 2341C-T transition resulting in a pro724-to-leu (P724L) amino acid substitution. (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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Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. | De Franco E | Diabetes | 2017 | PMID: 28468959 |
Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. | Cagalinec M | PLoS biology | 2016 | PMID: 27434582 |
WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity. | Grenier J | Ophthalmology | 2016 | PMID: 27395765 |
Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders. | Chaussenot A | Clinical genetics | 2015 | PMID: 24890733 |
Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features. | Matsunaga K | PloS one | 2014 | PMID: 25211237 |
Calcium efflux from the endoplasmic reticulum leads to β-cell death. | Hara T | Endocrinology | 2014 | PMID: 24424032 |
β-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. | Shang L | Diabetes | 2014 | PMID: 24227685 |
The E3 ligase Smurf1 regulates Wolfram syndrome protein stability at the endoplasmic reticulum. | Guo X | The Journal of biological chemistry | 2011 | PMID: 21454619 |
Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. | Fonseca SG | The Journal of clinical investigation | 2010 | PMID: 20160352 |
Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin. | Hofmann S | FEBS letters | 2006 | PMID: 16806192 |
WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. | Fonseca SG | The Journal of biological chemistry | 2005 | PMID: 16195229 |
A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). | Inoue H | Nature genetics | 1998 | PMID: 9771706 |
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Text-mined citations for rs28937890 ...
HelpRecord last updated May 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.