NM_006005.3(WFS1):c.1123C>T (p.Arg375Cys) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 19, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001857735.6

Allele description [Variation Report for NM_006005.3(WFS1):c.1123C>T (p.Arg375Cys)]

NM_006005.3(WFS1):c.1123C>T (p.Arg375Cys)

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.1123C>T (p.Arg375Cys)

HGVS:

NC_000004.12:g.6300918C>T
NG_011700.1:g.36069C>T
NM_001145853.1:c.1123C>T
NM_006005.3:c.1123C>TMANE SELECT
NP_001139325.1:p.Arg375Cys
NP_005996.2:p.Arg375Cys
LRG_1417t1:c.1123C>T
LRG_1417:g.36069C>T
LRG_1417p1:p.Arg375Cys
NC_000004.11:g.6302645C>T

Protein change:

R375C

Links:

dbSNP: rs200095753

NCBI 1000 Genomes Browser:

rs200095753

Molecular consequence:

NM_001145853.1:c.1123C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.1123C>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
SCV002189650	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29563951, 31264968, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002189650

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 19, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic Testing for Wolfram Syndrome Mutations in a Sample of 71 Patients with Hereditary Optic Neuropathy and Negative Genetic Test Results for OPA1/OPA3/LHON.

Galvez-Ruiz A, Galindo-Ferreiro A, Schatz P.

Neuroophthalmology. 2018 Apr;42(2):73-82. doi: 10.1080/01658107.2017.1344252.

PubMed [citation]

PMID:: 29563951
PMCID:: PMC5858862

Residual β cell function and monogenic variants in long-duration type 1 diabetes patients.

Yu MG, Keenan HA, Shah HS, Frodsham SG, Pober D, He Z, Wolfson EA, D'Eon S, Tinsley LJ, Bonner-Weir S, Pezzolesi MG, King GL.

J Clin Invest. 2019 Jul 2;129(8):3252-3263. doi: 10.1172/JCI127397.

PubMed [citation]

PMID:: 31264968
PMCID:: PMC6668678

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002189650.3

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the WFS1 protein (p.Arg375Cys). This variant is present in population databases (rs200095753, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of autosomal dominant Wolfram-like syndrome (PMID: 29563951, 31264968). ClinVar contains an entry for this variant (Variation ID: 215384). 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 80%. 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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