VCV000137915.33 - ClinVar

NM_006005.3(WFS1):c.1797C>A (p.Val599=)

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.

(12)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006005.3(WFS1):c.1797C>A (p.Val599=)

Variation ID: 137915 Accession: VCV000137915.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.1 4: 6301592 (GRCh38) [ NCBI UCSC ] 4: 6303319 (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	Oct 11, 2015	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006005.3:c.1797C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005996.2:p.Val599=	synonymous
NM_001145853.1:c.1797C>A	NP_001139325.1:p.Val599=	synonymous
NC_000004.12:g.6301592C>A
NC_000004.11:g.6303319C>A
NG_011700.1:g.36743C>A
LRG_1417:g.36743C>A
LRG_1417t1:c.1797C>A	LRG_1417p1:p.Val599=

... more HGVS ... less HGVS

Protein change

Other names

p.V599V:GTC>GTA

Canonical SPDI

NC_000004.12:6301591:C:A

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.

0.01038 (A)

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

1000 Genomes Project 0.01038

Trans-Omics for Precision Medicine (TOPMed) 0.01094

1000 Genomes Project 30x 0.01156

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01215

Links

ClinGen: CA295797 dbSNP: rs71524361 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	1753	1854

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.
not specified	Benign (4)	criteria provided, multiple submitters, no conflicts	Apr 22, 2013	RCV000155409.16
WFS1-Related Spectrum Disorders	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000273823.13
Autosomal dominant nonsyndromic hearing loss 6	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000368428.13
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000865310.25
Wolfram syndrome 1	Benign (1)	criteria provided, single submitter	-	RCV003126506.8
Autosomal dominant nonsyndromic hearing loss 6 Cataract 41 Type 2 diabetes mellitus Wolfram syndrome 1 Wolfram-like syndrome	Likely benign (1)	criteria provided, single submitter	Sep 27, 2021	RCV002505090.8

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.
Benign (Apr 22, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000169825.12 First in ClinVar: Jun 23, 2014 Last updated: Oct 11, 2015	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (May 07, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000205096.5 First in ClinVar: Jan 31, 2015 Last updated: Oct 11, 2015	Comment: "Val599Val in Exon 08 of WFS1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, … (more) "Val599Val in Exon 08 of WFS1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 3.3% (122/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs71524361)." (less) Number of individuals with the variant: 15
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal dominant nonsyndromic hearing loss 6 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000450636.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	WFS1-Related Spectrum Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000450637.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (Sep 27, 2021)	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: SCV002807070.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005298386.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Mar 23, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001472974.3 First in ClinVar: Jan 26, 2021 Last updated: Mar 04, 2023
Benign (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Wolfram syndrome 1 (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV003802900.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Publications: PubMed (6) PubMed: 20738327‚ 33879153‚ 12955714‚ 18060660‚ 20301750‚ 17603484 Comment: Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However … (more) Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs71524361 in Wolfram's syndrome yet. (less)
Benign (Jan 31, 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: SCV001006253.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959178.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001969123.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035496.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

"Val599Val in Exon 08 of WFS1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 3.3% (122/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs71524361)."

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs71524361 in Wolfram's syndrome yet.

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
WFS1 Spectrum Disorder.	Adam MP	-	2022	PMID: 20301750
A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1.	Gong Y	BMC endocrine disorders	2021	PMID: 33879153
Wolfram syndrome and WFS1 gene.	Rigoli L	Clinical genetics	2011	PMID: 20738327
Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program.	Florez JC	Diabetologia	2008	PMID: 18060660
Common variants in WFS1 confer risk of type 2 diabetes.	Sandhu MS	Nature genetics	2007	PMID: 17603484
Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease.	Cryns K	Human mutation	2003	PMID: 12955714

Text-mined citations for rs71524361 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_006005.3(WFS1):c.1797C>A (p.Val599=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs71524361 ...