NM_006005.3(WFS1):c.1230_1233del (p.Val412fs) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000494474.16

Allele description [Variation Report for NM_006005.3(WFS1):c.1230_1233del (p.Val412fs)]

NM_006005.3(WFS1):c.1230_1233del (p.Val412fs)

Gene:

WFS1:wolframin ER transmembrane glycoprotein [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

4p16.1

Genomic location:

Preferred name:

NM_006005.3(WFS1):c.1230_1233del (p.Val412fs)

HGVS:

NC_000004.12:g.6301023CT[1]
NG_011700.1:g.36174CT[1]
NM_001145853.1:c.1230_1233del
NM_006005.3:c.1228_1231delCTCT
NM_006005.3:c.1230_1233delMANE SELECT
NP_001139325.1:p.Val412fs
NP_005996.2:p.Val412fs
LRG_1417t1:c.1230_1233del
LRG_1417:g.36174CT[1]
LRG_1417p1:p.Val412fs
NC_000004.11:g.6302750CT[1]
NC_000004.11:g.6302750_6302753del
NM_006005.3:c.1228_1231delMANE SELECT
NM_006005.3:c.1228_1231delCTCTMANE SELECT
NM_006005.3:c.1230_1233del
NM_006005.3:c.1230_1233delCTCTMANE SELECT

Protein change:

V412fs

Links:

OMIM: 606201.0030; dbSNP: rs760337383

NCBI 1000 Genomes Browser:

rs760337383

Molecular consequence:

NM_001145853.1:c.1230_1233del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_006005.3:c.1230_1233del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000582399	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 18, 2022)	germline	clinical testing	Citation Link,
SCV002035127	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002037029	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002232144	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11295831, 15605410, 22238590, 31600780, 28492532
SCV003821850	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of novel WFS1 mutations in Italian children with Wolfram syndrome.

Tessa A, Carbone I, Matteoli MC, Bruno C, Patrono C, Patera IP, De Luca F, Lorini R, Santorelli FM.

Hum Mutat. 2001 Apr;17(4):348-9.

PubMed [citation]

PMID:: 11295831

Wolfram syndrome in French population: characterization of novel mutations and polymorphisms in the WFS1 gene.

Giuliano F, Bannwarth S, Monnot S, Cano A, Chabrol B, Vialettes B, Delobel B, Paquis-Flucklinger V; French Group of WS.

Hum Mutat. 2005 Jan;25(1):99-100.

PubMed [citation]

PMID:: 15605410

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000582399.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV002035127.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002037029.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002232144.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003821850.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2025

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