NM_006005.3(WFS1):c.2206G>A (p.Gly736Ser) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 2, 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:: RCV001797328.11

Allele description [Variation Report for NM_006005.3(WFS1):c.2206G>A (p.Gly736Ser)]

NM_006005.3(WFS1):c.2206G>A (p.Gly736Ser)

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.2206G>A (p.Gly736Ser)

Other names:

NG_011700.1:g.37152G>A; NP_005996.2:p.(Gly736Ser)

HGVS:

NC_000004.12:g.6302001G>A
NG_011700.1:g.37152G>A
NM_001145853.1:c.2206G>A
NM_006005.3:c.2206G>AMANE SELECT
NP_001139325.1:p.Gly736Ser
NP_005996.2:p.Gly736Ser
LRG_1417t1:c.2206G>A
LRG_1417:g.37152G>A
LRG_1417p1:p.Gly736Ser
NC_000004.11:g.6303728G>A

Protein change:

G736S

Links:

dbSNP: rs71532864

NCBI 1000 Genomes Browser:

rs71532864

Molecular consequence:

NM_001145853.1:c.2206G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.2206G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Mus musculus chromodomain helicase DNA binding protein 3 (Chd3), tran...
PREDICTED: Mus musculus chromodomain helicase DNA binding protein 3 (Chd3), transcript variant X1, mRNA
gi|1720365299|ref|XM_017314455.2|

Nucleotide
ena/VASP-like protein isoform X1 [Ornithorhynchus anatinus]
ena/VASP-like protein isoform X1 [Ornithorhynchus anatinus]
gi|1626023679|ref|XP_028926251.1|

Protein
PREDICTED: Mus musculus transcription factor AP4 (Tfap4), transcript variant X6,...
PREDICTED: Mus musculus transcription factor AP4 (Tfap4), transcript variant X6, mRNA
gi|1720388046|ref|XM_011246047.3|

Nucleotide
MULTISPECIES: AcrZ family multidrug efflux pump-associated protein [Proteus]
MULTISPECIES: AcrZ family multidrug efflux pump-associated protein [Proteus]
gi|490367896|ref|WP_004247559.1|

Protein
Homo sapiens cDNA: FLJ21581 fis, clone COL06796
Homo sapiens cDNA: FLJ21581 fis, clone COL06796
gi|10437704|dbj|AK025234.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002038782	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jun 2, 2024)	germline	clinical testing	Citation Link,
SCV002236433	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8808601, 10521293, 32179840, 28492532
SCV004100830	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 21, 2022)	germline	research	PubMed (5) [See all records that cite these PMIDs] 8808601, 10521293, 32179840, 28492532, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002038782

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Jun 2, 2024)

germline

clinical testing

Citation Link,

SCV002236433

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 21, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004100830

Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 21, 2022)

germline

research

PubMed (5)
[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	2	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity.

Collier DA, Barrett TG, Curtis D, Macleod A, Arranz MJ, Maassen JA, Bundey S.

Am J Hum Genet. 1996 Oct;59(4):855-63.

PubMed [citation]

PMID:: 8808601
PMCID:: PMC1914816

Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1.

Hardy C, Khanim F, Torres R, Scott-Brown M, Seller A, Poulton J, Collier D, Kirk J, Polymeropoulos M, Latif F, Barrett T.

Am J Hum Genet. 1999 Nov;65(5):1279-90.

PubMed [citation]

PMID:: 10521293
PMCID:: PMC1288280

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV002038782.3

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

Description

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: 31264968, 15473915, 15605410, 32179840, 37185285, 37931151, Abali2023[article], 33841295, 8808601, 38162681, 35452662, 37383390, 36964972, 37444722, 10521293)

#	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, SCV002236433.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 1328696). This missense change has been observed in individuals with Wolfram syndrome (PMID: 8808601, 10521293, 32179840). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs71532864, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 736 of the WFS1 protein (p.Gly736Ser).

#	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

From Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar, SCV004100830.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	PubMed (5)

#	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		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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