NM_006005.3(WFS1):c.2108G>A (p.Arg703His) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Apr 22, 2022
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:: RCV001723374.11

Allele description [Variation Report for NM_006005.3(WFS1):c.2108G>A (p.Arg703His)]

NM_006005.3(WFS1):c.2108G>A (p.Arg703His)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.1

Genomic location:

Preferred name:

NM_006005.3(WFS1):c.2108G>A (p.Arg703His)

HGVS:

NC_000004.12:g.6301903G>A
NG_011700.1:g.37054G>A
NM_001145853.1:c.2108G>A
NM_006005.3:c.2108G>AMANE SELECT
NP_001139325.1:p.Arg703His
NP_005996.2:p.Arg703His
LRG_1417t1:c.2108G>A
LRG_1417:g.37054G>A
LRG_1417p1:p.Arg703His
NC_000004.11:g.6303630G>A

Protein change:

R703H

Links:

dbSNP: rs1323852277

NCBI 1000 Genomes Browser:

rs1323852277

Molecular consequence:

NM_001145853.1:c.2108G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.2108G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001958984	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001971837	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002032555	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 7, 2021)	germline	clinical testing	Citation Link,
SCV003525597	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21356526, 33297549, 28492532

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 two novel missense WFS1 mutations, H696Y and R703H, in patients with non-syndromic low-frequency sensorineural hearing loss.

Sun Y, Cheng J, Lu Y, Li J, Lu Y, Jin Z, Dai P, Wang R, Yuan H.

J Genet Genomics. 2011 Feb;38(2):71-6. doi: 10.1016/j.jcg.2011.01.001. Epub 2011 Feb 23.

PubMed [citation]

PMID:: 21356526

Improving the Management of Patients with Hearing Loss by the Implementation of an NGS Panel in Clinical Practice.

García-García G, Berzal-Serrano A, García-Díaz P, Villanova-Aparisi R, Juárez-Rodríguez S, de Paula-Vernetta C, Cavallé-Garrido L, Jaijo T, Armengot-Carceller M, Millán JM, Aller E.

Genes (Basel). 2020 Dec 7;11(12). doi: 10.3390/genes11121467.

PubMed [citation]

PMID:: 33297549
PMCID:: PMC7762334

See all PubMed Citations (3)

Details of each submission

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001958984.1

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001971837.1

#	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 GeneDx, SCV002032555.2

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

Description

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33297549, 21356526, 27535533)

#	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, SCV003525597.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 1297606). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 21356526, 33297549). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 703 of the WFS1 protein (p.Arg703His).

#	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: Apr 28, 2025

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