NM_006005.3(WFS1):c.1124G>A (p.Arg375His) AND not provided

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Sep 9, 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:: RCV000762133.35

Allele description [Variation Report for NM_006005.3(WFS1):c.1124G>A (p.Arg375His)]

NM_006005.3(WFS1):c.1124G>A (p.Arg375His)

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.1124G>A (p.Arg375His)

HGVS:

NC_000004.12:g.6300919G>A
NG_011700.1:g.36070G>A
NM_001145853.1:c.1124G>A
NM_006005.3:c.1124G>AMANE SELECT
NP_001139325.1:p.Arg375His
NP_005996.2:p.Arg375His
LRG_1417t1:c.1124G>A
LRG_1417:g.36070G>A
LRG_1417p1:p.Arg375His
NC_000004.11:g.6302646G>A

Protein change:

R375H

Links:

dbSNP: rs142671083

NCBI 1000 Genomes Browser:

rs142671083

Molecular consequence:

NM_001145853.1:c.1124G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.1124G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000892391	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	Citation Link,
SCV001494165	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31264968, 31638168, 28492532
SCV001740836	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001814117	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 9, 2024)	germline	clinical testing	Citation Link,
SCV001972566	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV002036812	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing

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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Whole‑exome sequencing in Russian children with non‑type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY‑related and unrelated genes.

Glotov OS, Serebryakova EA, Turkunova ME, Efimova OA, Glotov AS, Barbitoff YA, Nasykhova YA, Predeus AV, Polev DE, Fedyakov MA, Polyakova IV, Ivashchenko TE, Shved NY, Shabanova ES, Tiselko AV, Romanova OV, Sarana AM, Pendina AA, Scherbak SG, Musina EV, Petrovskaia-Kaminskaia AV, Lonishin LR, et al.

Mol Med Rep. 2019 Dec;20(6):4905-4914. doi: 10.3892/mmr.2019.10751. Epub 2019 Oct 16.

PubMed [citation]

PMID:: 31638168
PMCID:: PMC6854535

See all PubMed Citations (3)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV000892391.28

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001494165.4

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 375 of the WFS1 protein (p.Arg375His). This variant is present in population databases (rs142671083, gnomAD 0.05%). This missense change has been observed in individual(s) with WFS1-related coditions (PMID: 31264968, 31638168). ClinVar contains an entry for this variant (Variation ID: 504709). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. 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

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001740836.3

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

From GeneDx, SCV001814117.2

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

Description

Identified as heterozygous without a second variant in WFS1 in individuals with diabetes who had different genetic etiologies for their phenotypes (PMID: 31264968, 31638168); 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: 34426522, 26435059, 31638168, 31264968, 37444722, 32483926, 36672845)

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001972566.1

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

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036812.1

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

Last Updated: Nov 3, 2024

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