ClinVar Genomic variation as it relates to human health
NM_006005.3(WFS1):c.1230_1233del (p.Val412fs)
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
-
NM_006005.3(WFS1):c.1230_1233del (p.Val412fs)
Variation ID: 429753 Accession: VCV000429753.34
- Type and length
-
Microsatellite, 4 bp
- Location
-
Cytogenetic: 4p16.1 4: 6301023-6301026 (GRCh38) [ NCBI UCSC ] 4: 6302750-6302753 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006005.3:c.1228_1231del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_006005.3:c.1228_1231delCTCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_006005.3:c.1230_1233del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005996.2:p.Val412fs frameshift NM_006005.3:c.1230_1233delCTCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_001145853.1:c.1230_1233del NP_001139325.1:p.Val412fs frameshift NC_000004.12:g.6301023CT[1] NC_000004.11:g.6302750CT[1] NG_011700.1:g.36174CT[1] LRG_1417:g.36174CT[1] LRG_1417t1:c.1230_1233del LRG_1417p1:p.Val412fs - Protein change
- V412fs
- Other names
- -
- Canonical SPDI
- NC_000004.12:6301022:CTCTCT:CT
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| WFS1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1752 | 1853 | |
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
Help
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 25, 2023 | RCV000494474.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 2, 2018 | RCV000778738.6 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 22, 2024 | RCV001672804.10 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV002252138.5 |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 24, 2021 | RCV002481565.3 | |
|
WFS1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Sep 25, 2023 | RCV004535551.1 |
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
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
WFS1-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915096.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The WFS1 c.1230_1233delCTCT (p.Val412SerfsTer29) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the … (more)
The WFS1 c.1230_1233delCTCT (p.Val412SerfsTer29) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Val412SerfsTer29 variant, also known as c.1228_1231delCTCT and c.1234_1237delGTCT, has been identified in a homozygous state in 10 individuals and in a compound heterozygous state in 19 individuals, all of whom were diagnosed with Wolfram syndrome (Giuliano et al. 2005; d'Annunzio et al. 2008; Gasparin et al. 2009; Chaussenot et al. 2011; Sobhani et al. 2013; Aloi et al. 2013; Bischoff et al. 2015; Pedroso et al. 2015). To date, this variant has not been reported in association with autosomal dominant phenotypes. This variant was absent from 200 control chromosomes (Gasparin et al. 2009; Aloi et al. 2013) and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and the potential impact of frameshift variants, the p. Val412SerfsTer29 variant is classified as pathogenic for WFS1-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Wolfram syndrome 1
Affected status: yes
Allele origin:
germline
|
Molecular Endocrinology Laboratory, Christian Medical College
Accession: SCV001890913.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
|
Pathogenic
(Dec 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cataract 41
Type 2 diabetes mellitus Wolfram syndrome 1 Autosomal dominant nonsyndromic hearing loss 6 Wolfram-like syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002777856.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jul 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582399.6
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with … (more)
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20972738, 20738327, 27412528, 18566338, 29728875, 26025012, 11295831, 19042979, 12955714, 15605410, 23845777, 22238590, 29183106, 31600780, 32005694, 31589614, 34356170) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Wolfram syndrome 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047052.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The WFS1 c.1230_1233del (p.Val412SerfsTer29) variant has been reported in homozygous state in individuals affected with Wolfram syndrome 1 (Tessa et al., 2001). This variant is … (more)
The WFS1 c.1230_1233del (p.Val412SerfsTer29) variant has been reported in homozygous state in individuals affected with Wolfram syndrome 1 (Tessa et al., 2001). This variant is reported with the allele frequency (0.003536%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. This variant causes a frameshift starting with codon Valine 412, changes this amino acid to Serine residue, and creates a premature Stop codon at position 29 of the new reading frame, denoted p.Val412SerfsTer29. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the endocrine system (present) , Sensorineural hearing loss disorder (present) , Abnormality of the nervous system (present)
|
|
|
Pathogenic
(Sep 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
WFS1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004118215.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The WFS1 c.1230_1233delCTCT variant is predicted to result in a frameshift and premature protein termination (p.Val412Serfs*29). This variant has been reported to be causative for … (more)
The WFS1 c.1230_1233delCTCT variant is predicted to result in a frameshift and premature protein termination (p.Val412Serfs*29). This variant has been reported to be causative for autosomal recessive Wolfram syndrome (Reported as 1387delCTCT in Tessa et al. 2001. PubMed ID: 11295831; Marshall et al. 2013. PubMed ID: 23981289). It is interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/429753). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6302749-GCTCT-G). Frameshift variants in WFS1 are a commonly documented cause of Wolfram syndrome (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). In summary, this variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Dec 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003821850.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523050.2
First in ClinVar: Jun 09, 2022 Last updated: Feb 04, 2024 |
Comment:
ACMG classification criteria: PVS1_strong, PM2_supporting, PM3_very strong, PP4_supporting
Clinical Features:
Neurodevelopmental abnormality (present) , Autistic behavior (present) , Abnormal facial shape (present)
|
|
|
Pathogenic
(Dec 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002232144.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val412Serfs*29) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Val412Serfs*29) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 479 amino acid(s) of the WFS1 protein. This variant is present in population databases (rs760337383, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 11295831, 15605410, 22238590, 31600780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429753). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Wolfram syndrome 1
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807743.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 28, 2024 |
Comment:
ACMG classification criteria: PVS1 strong, PM3 very strong, PM2 supporting, PP4 supporting.
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Visual impairment (present) , Cerebral visual impairment (present) , Obesity (present) , Attention deficit hyperactivity disorder (present) , Central diabetes insipidus (present) , Atypical behavior … (more)
Visual impairment (present) , Cerebral visual impairment (present) , Obesity (present) , Attention deficit hyperactivity disorder (present) , Central diabetes insipidus (present) , Atypical behavior (present) , Skin-picking (present) , Mutism (present) , Diabetes mellitus (present) , Increased body weight (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Visual impairment (present) , Cerebral visual impairment (present) , Sensorineural hearing loss disorder (present) , Bilateral sensorineural hearing impairment (present) , Adult onset sensorineural hearing … (more)
Visual impairment (present) , Cerebral visual impairment (present) , Sensorineural hearing loss disorder (present) , Bilateral sensorineural hearing impairment (present) , Adult onset sensorineural hearing impairment (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035127.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037029.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Pathogenic
(Apr 01, 2001)
|
no assertion criteria provided
Method: literature only
|
WOLFRAM SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044808.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
For discussion of the 4-bp deletion in the WFS1 gene (1387delCTCT) that was found in compound heterozygous state in a patient with Wolfram syndrome (WFS1; … (more)
For discussion of the 4-bp deletion in the WFS1 gene (1387delCTCT) that was found in compound heterozygous state in a patient with Wolfram syndrome (WFS1; 222300) by Tessa et al. (2001), see 606201.0028. (less)
|
|
| click to load more click to collapse | |||||
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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional assessment of variants associated with Wolfram syndrome. | Riachi M | Human molecular genetics | 2019 | PMID: 31600780 |
| Selective cognitive and psychiatric manifestations in Wolfram Syndrome. | Bischoff AN | Orphanet journal of rare diseases | 2015 | PMID: 26025012 |
| Association of optic atrophy and type 1 diabetes: clinical hallmarks for the diagnosis of Wolfram syndrome. | Pedroso JL | Arquivos de neuro-psiquiatria | 2015 | PMID: 26017216 |
| Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms. | Sobhani M | Gene | 2013 | PMID: 23845777 |
| Wolfram syndrome: new mutations, different phenotype. | Aloi C | PloS one | 2012 | PMID: 22238590 |
| Neurologic features and genotype-phenotype correlation in Wolfram syndrome. | Chaussenot A | Annals of neurology | 2011 | PMID: 21446023 |
| Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome. | Gasparin MR | European journal of endocrinology | 2009 | PMID: 19042979 |
| Wolfram syndrome (diabetes insipidus, diabetes, optic atrophy, and deafness): clinical and genetic study. | d'Annunzio G | Diabetes care | 2008 | PMID: 18566338 |
| Wolfram syndrome in French population: characterization of novel mutations and polymorphisms in the WFS1 gene. | Giuliano F | Human mutation | 2005 | PMID: 15605410 |
| Identification of novel WFS1 mutations in Italian children with Wolfram syndrome. | Tessa A | Human mutation | 2001 | PMID: 11295831 |
Text-mined citations for rs760337383 ...
HelpRecord last updated Oct 27, 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.