ClinVar Genomic variation as it relates to human health
NM_006005.3(WFS1):c.529C>T (p.Arg177Cys)
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.
Likely pathogenic(2); Likely risk allele(1); 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.529C>T (p.Arg177Cys)
Variation ID: 809614 Accession: VCV000809614.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.1 4: 6291265 (GRCh38) [ NCBI UCSC ] 4: 6292992 (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 Feb 3, 2020 Oct 8, 2024 Jul 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006005.3:c.529C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005996.2:p.Arg177Cys missense NM_001145853.1:c.529C>T NP_001139325.1:p.Arg177Cys missense NC_000004.12:g.6291265C>T NC_000004.11:g.6292992C>T NG_011700.1:g.26416C>T LRG_1417:g.26416C>T LRG_1417t1:c.529C>T LRG_1417p1:p.Arg177Cys - Protein change
- R177C
- Other names
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- Canonical SPDI
- NC_000004.12:6291264: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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
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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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WFS1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1742 | 1843 |
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
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 21, 2023 | RCV000998213.29 | |
Likely risk allele (1) |
criteria provided, single submitter
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- | RCV002509116.1 | |
WFS1-related disorder
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Likely pathogenic (1) |
no assertion criteria provided
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Mar 13, 2024 | RCV004738111.1 |
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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Likely pathogenic
(Jul 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001154159.26
First in ClinVar: Feb 03, 2020 Last updated: Oct 08, 2024 |
Comment:
WFS1: PM2, PM3, PM5, PP3
Number of individuals with the variant: 2
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Uncertain significance
(Sep 11, 2020)
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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: SCV001757138.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29183106) (less)
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Likely 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: SCV002773843.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 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 rs760631912 in Wolfram's syndrome yet. (less)
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Likely pathogenic
(Jul 21, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003262966.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg177 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18660851). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 809614). This missense change has been observed in individual(s) with clinical features of autosomal recessive WFS1-related conditions (PMID: 29183106, 33841295; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 177 of the WFS1 protein (p.Arg177Cys). (less)
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Likely pathogenic
(Mar 13, 2024)
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no assertion criteria provided
Method: clinical testing
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WFS1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005360302.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The WFS1 c.529C>T variant is predicted to result in the amino acid substitution p.Arg177Cys. This variant has been reported in the homozygous state in two … (more)
The WFS1 c.529C>T variant is predicted to result in the amino acid substitution p.Arg177Cys. This variant has been reported in the homozygous state in two unrelated individuals with Wolfram syndrome type 1 (Şıklar et al. 2018. PubMed ID: 29183106; Du et al. 2023. PubMed ID: 37974252). This variant has also been observed in the heterozygous state in a patient with optic atrophy (Charif et al. 2021. PubMed ID: 33841295). This variant is reported in a single individual (0.0029% of alleles) of Latino descent in gnomAD. Other missense variants at the same amino acid position (p.Arg177Pro, p.Arg177Ser) have been reported as disease-causing in multiple families with WFS1-related disease (Zenteno et al. 2008. PubMed ID: 18660851; Patel et al. 2022. PubMed ID: 34686905; Du et al. 2023. PubMed ID: 37974252). This variant is interpreted as likely pathogenic. (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 |
Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy. | Charif M | Frontiers in neurology | 2021 | PMID: 33841295 |
Monogenic Diabetes Not Caused By Mutations in Mody Genes: A Very Heterogenous Group of Diabetes. | Şıklar Z | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2018 | PMID: 29183106 |
Wolfram syndrome and WFS1 gene. | Rigoli L | Clinical genetics | 2011 | PMID: 20738327 |
Familial Wolfram syndrome due to compound heterozygosity for two novel WFS1 mutations. | Zenteno JC | Molecular vision | 2008 | PMID: 18660851 |
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 rs760631912 ...
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.