ClinVar Genomic variation as it relates to human health
NM_006005.3(WFS1):c.124C>T (p.Arg42Ter)
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.124C>T (p.Arg42Ter)
Variation ID: 189251 Accession: VCV000189251.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.1 4: 6277579 (GRCh38) [ NCBI UCSC ] 4: 6279306 (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 Apr 1, 2015 May 1, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006005.3:c.124C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005996.2:p.Arg42Ter nonsense NM_001145853.1:c.124C>T NP_001139325.1:p.Arg42Ter nonsense NC_000004.12:g.6277579C>T NC_000004.11:g.6279306C>T NG_011700.1:g.12730C>T LRG_1417:g.12730C>T LRG_1417t1:c.124C>T LRG_1417p1:p.Arg42Ter - Protein change
- R42*
- Other names
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- Canonical SPDI
- NC_000004.12:6277578: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD) 0.00013
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
Exome Aggregation Consortium (ExAC) 0.00017
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
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 |
1725 | 1825 |
Conditions - Germline
Condition
Help
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
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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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 22, 2023 | RCV000169684.9 | |
not provided (1) |
no classification provided
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- | RCV000509458.4 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000514926.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 18, 2022 | RCV001536034.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2016 | RCV001199167.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2021 | RCV002515205.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2021 | RCV002467643.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2022 | RCV003398871.4 |
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
Help
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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Pathogenic
(Nov 19, 2013)
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criteria provided, single submitter
Method: clinical testing
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Wolfram syndrome
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000221222.2 First in ClinVar: Apr 01, 2015 Last updated: Apr 01, 2015 |
Comment:
The Arg42X variant in WFS1 has not been previously identified in individuals with Wolfram syndrome, but has been identified in 0.02% (1/8540) of European American … (more)
The Arg42X variant in WFS1 has not been previously identified in individuals with Wolfram syndrome, but has been identified in 0.02% (1/8540) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs71530923). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a pathogenic interpretation. This nonsense variant leads to a premature termination codon at position 42, which is predicted to lead to a truncated or absent protein. Heterozygous carries of pathogenic WFS1 variants may be at risk for developing low frequency sensorineural hearing loss and/or diabetes mellitus (Ohata 1998, Sandhu 2007, Franks 2008). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610547.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Type 2 diabetes mellitus
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370163.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5.
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Likely pathogenic
(-)
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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: SCV002738618.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs71530923 variant … (more)
Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs71530923 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. (less)
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Likely pathogenic
(Mar 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Wolfram syndrome 1
Wolfram-like syndrome
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV002764547.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The c.124C>T, p.Arg42Ter nonsense variant identified in WFS1 has been reported individuals with Wolfram syndrome [PMID:31980526], type 2 diabetes [PMID:20028947], and chronic progressive external ophthalmoplegia … (more)
The c.124C>T, p.Arg42Ter nonsense variant identified in WFS1 has been reported individuals with Wolfram syndrome [PMID:31980526], type 2 diabetes [PMID:20028947], and chronic progressive external ophthalmoplegia [PMID:31521625]. This variant is not reported in gnomAD v3 database, indicating this is a rare allele. This nonsense variant leads to a premature termination codon at position 42, which is predicted to lead to a truncated or absent protein. Heterozygous carries of pathogenic WFS1 variants may be at risk for developing low frequency sensorineural hearing loss and/or diabetes mellitus [PMID:18040659,17603484, 9856492]. Based on the available evidence, the variant c.124C>T, p.Arg42Ter in the WFS1 gene is classified as likely pathogenic. (less)
Clinical Features:
Hepatic steatosis (present)
Secondary finding: no
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Pathogenic
(Feb 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cataract 41
Type 2 diabetes mellitus Wolfram syndrome 1 Autosomal dominant nonsyndromic hearing loss 6 Wolfram-like syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752727.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
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Pathogenic
(May 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Wolfram syndrome 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933828.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: WFS1 c.124C>T (p.Arg42X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: WFS1 c.124C>T (p.Arg42X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.3e-05 in 194514 control chromosomes (i.e., 18 heterozygous carriers; gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.124C>T has been reported in the literature in at least one compound heterozygous individual affected with atypical late-onset Wolfram syndrome 1 (WFS1) without diabetes insipidus (e.g., Rigoli_2022), suggesting the variant is likely to be associated with autosomal recessive WFS1. The variant was also found to segregate with a maturity-onset diabetes of the young phenotype in at least one family (e.g., Saint-Martin_2022). Additionally, c.124C>T has been reported in heterozygous individuals affected with early-onset diabetes (e.g., Huopio_2016), chronic progressive external ophthalmoplegia (e.g., Heighton_2019), and intellectual and psychiatric disorders (e.g., Rigoli_2022, Valentino_2021), without strong evidence for causality. However, the variant was also identified in many healthy controls (e.g., Fawcett_2010, Billings_2022). These findings therefore do not allow conclusions about the association of the variant with autosomal-dominant Wolfram-like syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30245029, 36208030, 20028947, 31521625, 31980526, 27167055, 35206658, 34556497, 34356170). Nine ClinVar submitters (evaluation after 2014) have cited the variant and all submitters classified the variant as pathogenic (n = 4) or likely pathogenic (n = 5). Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive WFS1. (less)
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Pathogenic
(Aug 26, 2022)
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criteria provided, single submitter
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: SCV004104060.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The WFS1 c.124C>T variant is predicted to result in premature protein termination (p.Arg42*). This variant was reported in the heterozygous state in a patient with … (more)
The WFS1 c.124C>T variant is predicted to result in premature protein termination (p.Arg42*). This variant was reported in the heterozygous state in a patient with adult onset chronic progressive external ophthalmoplegia (Table S1, Heighton et al. 2019. PubMed ID: 31521625), in a study of patients with type 2 diabetes (Appendix Table 5, Fawcett et al. 2009. PubMed ID: 20028947), and in a patient with intellectual disability and autism spectrum disorder (Valentino et al. 2021. PubMed ID: 34356170). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6279306-C-T). Nonsense variants in WFS1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Aug 21, 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: SCV002027919.3
First in ClinVar: Nov 29, 2021 Last updated: Nov 25, 2023 |
Comment:
Identified in the heterozygous state in a patient with chronic progressive external ophthalmoplegia in the published literature, however, familial segregation studies could not be performed, … (more)
Identified in the heterozygous state in a patient with chronic progressive external ophthalmoplegia in the published literature, however, familial segregation studies could not be performed, and authors indicate that the association of this variant with the patient's phenotype is uncertain (Heighton et al., 2019); Identified in the heterozygous state in a patient with intellectual disability and autism spectrum disorder, however segregation of this variant is unknown and the patient was not reported with other features of a WFS1-related disorder (Valentino et al., 2021); Identified in a study of type 2 diabetics and controls in the literature (Fawcett et al., 2010); however, no specific information was provided; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 31980526, 33031055, 36208030, 34556497, 35206658, 36294752, 31521625, 34356170, 20028947) (less)
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Likely pathogenic
(Feb 08, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003814857.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 02, 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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Invitae
Accession: SCV002243968.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg42*) in the WFS1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg42*) in the WFS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WFS1 are known to be pathogenic (PMID: 12955714). This variant is present in population databases (rs71530923, gnomAD 0.01%). This variant has not been observed in the literature in individuals with autosomal recessive WFS1-related conditions. This variant has been reported in individual(s) with clinical features of autosomal dominant Wolfram-like syndrome (PMID: 31521625); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 189251). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2022)
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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: SCV002544860.10
First in ClinVar: Jul 09, 2022 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Likely pathogenic
(Sep 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003560140.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.124C>T (p.R42*) alteration, located in exon 2 (coding exon 1) of the WFS1 gene, consists of a C to T substitution at nucleotide position … (more)
The c.124C>T (p.R42*) alteration, located in exon 2 (coding exon 1) of the WFS1 gene, consists of a C to T substitution at nucleotide position 124. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 42.This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome and autosomal dominant WFS1-related low frequency sensorineural hearing loss; however, it would be expected to be causative of autosomal recessive WFS1-related Wolfram syndrome based on mechanism of disease. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (22/225882) total alleles studied. The highest observed frequency was 0.02% (17/97912) of European (non-Finnish) alleles. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Autosomal dominant nonsyndromic hearing loss 6
Wolfram syndrome 1 Wolfram-like syndrome
Affected status: unknown
Allele origin:
maternal
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GenomeConnect, ClinGen
Accession: SCV000607106.1
First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Decreased fetal movement (present) , Abnormal delivery (present) , Short stature (present) , Abnormality of the neck (present) , Oral-pharyngeal dysphagia (present) , Abnormality of … (more)
Decreased fetal movement (present) , Abnormal delivery (present) , Short stature (present) , Abnormality of the neck (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Ptosis (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of digit (present) , Abnormality of facial musculature (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the pelvis (present) , Feeding difficulties (present) , Abnormality of esophagus morphology (present) , Abnormality of the large intestine (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2015-01-27
Testing laboratory interpretation: Uncertain significance
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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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Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort. | Billings LK | Endocrinology, diabetes & metabolism | 2022 | PMID: 36208030 |
An Atypical Case of Late-Onset Wolfram Syndrome 1 without Diabetes Insipidus. | Rigoli L | International journal of environmental research and public health | 2022 | PMID: 35206658 |
Gene Panel Sequencing of Patients With Monogenic Diabetes Brings to Light Genes Typically Associated With Syndromic Presentations. | Saint-Martin C | Diabetes | 2022 | PMID: 34556497 |
Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations. | Valentino F | Brain sciences | 2021 | PMID: 34356170 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Genotypes of chronic progressive external ophthalmoplegia in a large adult-onset cohort. | Heighton JN | Mitochondrion | 2019 | PMID: 31521625 |
Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. | Azaiez H | American journal of human genetics | 2018 | PMID: 30245029 |
Clinical, Genetic, and Biochemical Characteristics of Early-Onset Diabetes in the Finnish Population. | Huopio H | The Journal of clinical endocrinology and metabolism | 2016 | PMID: 27167055 |
A systematic approach to the reporting of medically relevant findings from whole genome sequencing. | McLaughlin HM | BMC medical genetics | 2014 | PMID: 25714468 |
Detailed investigation of the role of common and low-frequency WFS1 variants in type 2 diabetes risk. | Fawcett KA | Diabetes | 2010 | PMID: 20028947 |
Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations. | Franks PW | Diabetologia | 2008 | PMID: 18040659 |
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 |
Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family. | Ohata T | Human genetics | 1998 | PMID: 9856492 |
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Text-mined citations for rs71530923 ...
HelpRecord last updated May 01, 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.