VCV000285046.41 - ClinVar

NM_006005.3(WFS1):c.2122C>T (p.Arg708Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006005.3(WFS1):c.2122C>T (p.Arg708Cys)

Variation ID: 285046 Accession: VCV000285046.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.1 4: 6301917 (GRCh38) [ NCBI UCSC ] 4: 6303644 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 14, 2017	Oct 20, 2024	Jan 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006005.3:c.2122C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005996.2:p.Arg708Cys	missense
NM_001145853.1:c.2122C>T	NP_001139325.1:p.Arg708Cys	missense
NC_000004.12:g.6301917C>T
NC_000004.11:g.6303644C>T
NG_011700.1:g.37068C>T
LRG_1417:g.37068C>T
LRG_1417t1:c.2122C>T	LRG_1417p1:p.Arg708Cys
	O76024:p.Arg708Cys

... more HGVS ... less HGVS

Protein change

R708C

Other names

Canonical SPDI

NC_000004.12:6301916:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00010

Exome Aggregation Consortium (ExAC) 0.00011

Trans-Omics for Precision Medicine (TOPMed) 0.00012

The Genome Aggregation Database (gnomAD) 0.00016

Links

ClinGen: CA2839605 UniProtKB: O76024#VAR_011311 dbSNP: rs200099217 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
WFS1		No evidence available	No evidence available	GRCh38 GRCh37	1756	1857

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Monogenic diabetes	Uncertain significance (1)	criteria provided, single submitter	Dec 16, 2015	RCV000445375.5
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 27, 2024	RCV000585352.35
Autosomal dominant nonsyndromic hearing loss 6 Cataract 41 Type 2 diabetes mellitus Wolfram syndrome 1 Wolfram-like syndrome	Uncertain significance (1)	criteria provided, single submitter	Apr 4, 2022	RCV002494843.4
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 28, 2022	RCV004021170.1
WFS1-related disorder	Uncertain significance (1)	no assertion criteria provided	Mar 28, 2024	RCV004535338.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Dec 16, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Monogenic diabetes Affected status: unknown Allele origin: unknown	Personalized Diabetes Medicine Program, University of Maryland School of Medicine Accession: SCV000537019.1 First in ClinVar: Mar 14, 2017 Last updated: Mar 14, 2017	Comment: ACMG Criteria: PP3 Number of individuals with the variant: 1
Uncertain significance (Dec 02, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000337893.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=WFS1 Number of individuals with the variant: 2 Sex: mixed
Uncertain significance (Nov 23, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001796221.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Reported previously in the heterozygous state in an individual with Wolfram syndrome who was also apparently homozygous for a WFS1 frameshift variant (Tessa et al., … (more) Reported previously in the heterozygous state in an individual with Wolfram syndrome who was also apparently homozygous for a WFS1 frameshift variant (Tessa et al., 2001).; Reported previously as a variant identified at a low frequency in individuals with type 1 diabetes (Awata et al., 2013); however, additional details were not provided to support the potential pathogenicity of this variant; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31264968, 23856252, 15368487, 20972738, 11295831, 26435059, 18688868) (less)
Uncertain significance (Apr 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cataract 41 Type 2 diabetes mellitus Wolfram syndrome 1 Autosomal dominant nonsyndromic hearing loss 6 Wolfram-like syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002776599.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely pathogenic (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002280011.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 11295831‚ 31264968 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 708 of the WFS1 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 708 of the WFS1 protein (p.Arg708Cys). This variant is present in population databases (rs200099217, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal recessive WFS1-related conditions (PMID: 11295831, 31264968; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285046). 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 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Uncertain significance (Jun 28, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004979918.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 11295831‚ 28432734 Comment: Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome and autosomal dominant WFS1-related low frequency sensorineural hearing loss Based on insufficient or conflicting evidence, … (more) Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome and autosomal dominant WFS1-related low frequency sensorineural hearing loss Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000693145.30 First in ClinVar: Mar 03, 2018 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Uncertain significance (Mar 28, 2024)	no assertion criteria provided Method: clinical testing	WFS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004117168.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The WFS1 c.2122C>T variant is predicted to result in the amino acid substitution p.Arg708Cys. This variant was reported in the heterozygous state in a patient … (more) The WFS1 c.2122C>T variant is predicted to result in the amino acid substitution p.Arg708Cys. This variant was reported in the heterozygous state in a patient with Wolfram syndrome, and was described as ‘probably neutral’ due the patient being homozygous for a different pathogenic premature termination variant (Tessa. 2001. PubMed ID: 11295831). This variant has also been described in a patient with type 1 diabetes (Table S6, Yu. 2019. PubMed ID: 31264968). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

Reported previously in the heterozygous state in an individual with Wolfram syndrome who was also apparently homozygous for a WFS1 frameshift variant (Tessa et al., 2001).; Reported previously as a variant identified at a low frequency in individuals with type 1 diabetes (Awata et al., 2013); however, additional details were not provided to support the potential pathogenicity of this variant; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31264968, 23856252, 15368487, 20972738, 11295831, 26435059, 18688868)

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 708 of the WFS1 protein (p.Arg708Cys). This variant is present in population databases (rs200099217, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal recessive WFS1-related conditions (PMID: 11295831, 31264968; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285046). 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 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome and autosomal dominant WFS1-related low frequency sensorineural hearing loss Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

The WFS1 c.2122C>T variant is predicted to result in the amino acid substitution p.Arg708Cys. This variant was reported in the heterozygous state in a patient with Wolfram syndrome, and was described as ‘probably neutral’ due the patient being homozygous for a different pathogenic premature termination variant (Tessa. 2001. PubMed ID: 11295831). This variant has also been described in a patient with type 1 diabetes (Table S6, Yu. 2019. PubMed ID: 31264968). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Residual β cell function and monogenic variants in long-duration type 1 diabetes patients.	Yu MG	The Journal of clinical investigation	2019	PMID: 31264968
Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.	Astuti D	Human mutation	2017	PMID: 28432734
Identification of novel WFS1 mutations in Italian children with Wolfram syndrome.	Tessa A	Human mutation	2001	PMID: 11295831
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=WFS1	-	-	-	-

Text-mined citations for rs200099217 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_006005.3(WFS1):c.2122C>T (p.Arg708Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200099217 ...