NM_006005.3(WFS1):c.2575C>T (p.Arg859Trp) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 26, 2021
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:: RCV001768230.7

Allele description [Variation Report for NM_006005.3(WFS1):c.2575C>T (p.Arg859Trp)]

NM_006005.3(WFS1):c.2575C>T (p.Arg859Trp)

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.2575C>T (p.Arg859Trp)

HGVS:

NC_000004.12:g.6302370C>T
NG_011700.1:g.37521C>T
NM_001145853.1:c.2575C>T
NM_006005.3:c.2575C>TMANE SELECT
NP_001139325.1:p.Arg859Trp
NP_005996.2:p.Arg859Trp
LRG_1417t1:c.2575C>T
LRG_1417:g.37521C>T
LRG_1417p1:p.Arg859Trp
NC_000004.11:g.6304097C>T

Protein change:

R859W

Links:

dbSNP: rs372298367

NCBI 1000 Genomes Browser:

rs372298367

Molecular consequence:

NM_001145853.1:c.2575C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.2575C>T - 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
SCV002008710	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 7, 2020)	germline	clinical testing	Citation Link,
SCV002263819	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 26, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18688868, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002008710

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 7, 2020)

germline

clinical testing

Citation Link,

SCV002263819

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 26, 2021)

germline

clinical testing

PubMed (2)
[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

Autoimmune disease in a DFNA6/14/38 family carrying a novel missense mutation in WFS1.

Hildebrand MS, Sorensen JL, Jensen M, Kimberling WJ, Smith RJ.

Am J Med Genet A. 2008 Sep 1;146A(17):2258-65. doi: 10.1002/ajmg.a.32449.

PubMed [citation]

PMID:: 18688868
PMCID:: PMC2586182

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV002008710.2

#	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 a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published in association with disease to our knowledge; This variant is associated with the following publications: (PMID: 26435059)

#	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, SCV002263819.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine with tryptophan at codon 859 of the WFS1 protein (p.Arg859Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs372298367, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg859 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18688868). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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