NM_006005.3(WFS1):c.1633G>A (p.Val545Met) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 16, 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:: RCV000732082.14

Allele description [Variation Report for NM_006005.3(WFS1):c.1633G>A (p.Val545Met)]

NM_006005.3(WFS1):c.1633G>A (p.Val545Met)

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.1633G>A (p.Val545Met)

Other names:

p.V545M:GTG>ATG

HGVS:

NC_000004.12:g.6301428G>A
NG_011700.1:g.36579G>A
NM_001145853.1:c.1633G>A
NM_006005.3:c.1633G>AMANE SELECT
NP_001139325.1:p.Val545Met
NP_005996.2:p.Val545Met
LRG_1417t1:c.1633G>A
LRG_1417:g.36579G>A
LRG_1417p1:p.Val545Met
NC_000004.11:g.6303155G>A

Protein change:

V545M

Links:

dbSNP: rs201993978

NCBI 1000 Genomes Browser:

rs201993978

Molecular consequence:

NM_001145853.1:c.1633G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.1633G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PLET1 placenta expressed transcript 1 [Homo sapiens]
PLET1 placenta expressed transcript 1 [Homo sapiens]
Gene ID:349633

Gene
349633[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000252531	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 16, 2024)	germline	clinical testing	Citation Link,
SCV000859987	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Feb 27, 2018)	germline	clinical testing	Citation Link,
SCV002232391	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 29, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29563951, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000252531

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 16, 2024)

germline

clinical testing

Citation Link,

SCV000859987

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL ClinVar v180209 classification definitions)

Uncertain significance
(Feb 27, 2018)

germline

clinical testing

Citation Link,

SCV002232391

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 29, 2023)

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	2	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

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, SCV000252531.13

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

Description

Reported heterozygous in an individual with Wolfram syndrome in whom a second variant was not described (PMID: 29563951); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29563951, 37713394)

#	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 Eurofins Ntd Llc (ga), SCV000859987.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002232391.3

#	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 valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 545 of the WFS1 protein (p.Val545Met). This variant is present in population databases (rs201993978, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Wolfram-like syndrome (PMID: 29563951). ClinVar contains an entry for this variant (Variation ID: 215391). 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 not expected to disrupt WFS1 protein function with a negative 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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