NM_006005.3(WFS1):c.2492G>A (p.Gly831Asp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 4, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000521055.11

Allele description [Variation Report for NM_006005.3(WFS1):c.2492G>A (p.Gly831Asp)]

NM_006005.3(WFS1):c.2492G>A (p.Gly831Asp)

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.2492G>A (p.Gly831Asp)

Other names:

WFS1, GLY831ASP (rs28937895)

HGVS:

NC_000004.12:g.6302287G>A
NG_011700.1:g.37438G>A
NM_001145853.1:c.2492G>A
NM_006005.3:c.2492G>AMANE SELECT
NP_001139325.1:p.Gly831Asp
NP_005996.2:p.Gly831Asp
LRG_1417t1:c.2492G>A
LRG_1417:g.37438G>A
LRG_1417p1:p.Gly831Asp
NC_000004.11:g.6304014G>A
O76024:p.Gly831Asp

Protein change:

G831D; GLY831ASP

Links:

UniProtKB: O76024#VAR_032968; OMIM: 606201.0017; dbSNP: rs28937895

NCBI 1000 Genomes Browser:

rs28937895

Molecular consequence:

NM_001145853.1:c.2492G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.2492G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617492	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jan 4, 2024)	germline	clinical testing	Citation Link,
SCV001559791	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 1, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11709537, 12073007, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617492

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Jan 4, 2024)

germline

clinical testing

Citation Link,

SCV001559791

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 1, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss.

Bespalova IN, Van Camp G, Bom SJ, Brown DJ, Cryns K, DeWan AT, Erson AE, Flothmann K, Kunst HP, Kurnool P, Sivakumaran TA, Cremers CW, Leal SM, Burmeister M, Lesperance MM.

Hum Mol Genet. 2001 Oct 15;10(22):2501-8.

PubMed [citation]

PMID:: 11709537
PMCID:: PMC6198816

Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations.

Cryns K, Pfister M, Pennings RJ, Bom SJ, Flothmann K, Caethoven G, Kremer H, Schatteman I, Köln KA, Tóth T, Kupka S, Blin N, Nürnberg P, Thiele H, van de Heyning PH, Reardon W, Stephens D, Cremers CW, Smith RJ, Van Camp G.

Hum Genet. 2002 May;110(5):389-94. Epub 2002 Apr 9.

PubMed [citation]

PMID:: 12073007

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000617492.3

#	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 (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12073007, 11709537, 37121227, 37808701)

#	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, SCV001559791.4

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 831 of the WFS1 protein (p.Gly831Asp). This variant is present in population databases (rs28937895, gnomAD 0.002%). This missense change has been observed in individual(s) with deafness (PMID: 11709537, 12073007). ClinVar contains an entry for this variant (Variation ID: 4523). 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 with a positive predictive value of 95%. 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.

#	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: Sep 29, 2024

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