VCV002203531.3 - ClinVar

NM_006005.3(WFS1):c.2390A>T (p.Asp797Val)

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.

(2)

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
Pathogenic(1); Uncertain significance(1)

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.2390A>T (p.Asp797Val)

Variation ID: 2203531 Accession: VCV002203531.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.1 4: 6302185 (GRCh38) [ NCBI UCSC ] 4: 6303912 (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	Feb 8, 2023	Jul 23, 2024	Jan 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006005.3:c.2390A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005996.2:p.Asp797Val	missense
NM_001145853.1:c.2390A>T	NP_001139325.1:p.Asp797Val	missense
NC_000004.12:g.6302185A>T
NC_000004.11:g.6303912A>T
NG_011700.1:g.37336A>T
LRG_1417:g.37336A>T
LRG_1417t1:c.2390A>T	LRG_1417p1:p.Asp797Val

... more HGVS ... less HGVS

Protein change

D797V

Other names

Canonical SPDI

NC_000004.12:6302184:A: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.

Links

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.
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 9, 2024	RCV002651817.4

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 (Jul 29, 2023)	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: SCV003525510.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 25250959‚ 29447883‚ 21602428‚ 26875006‚ 33841295 Comment: 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 … (more) 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. This variant disrupts the p.Asp797 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25250959, 29447883). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 2203531). This missense change has been observed in individual(s) with WFS1-related conditions (PMID: 21602428, 26875006, 33841295). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 797 of the WFS1 protein (p.Asp797Val). (less)
Pathogenic (Jan 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005078483.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: Identified in a patient with optic atrophy, sensorineural hearing loss, and diabetes in published literature (PMID: 26875006); Not observed at significant frequency in large population … (more) Identified in a patient with optic atrophy, sensorineural hearing loss, and diabetes in published literature (PMID: 26875006); Not observed at significant frequency in large population cohorts (gnomAD); 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: 37041640, 33841295, 35469785, 25250959, 29447883, 34387732, 26875006, 21602428) (less)

Comment:

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. This variant disrupts the p.Asp797 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25250959, 29447883). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 2203531). This missense change has been observed in individual(s) with WFS1-related conditions (PMID: 21602428, 26875006, 33841295). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 797 of the WFS1 protein (p.Asp797Val).

Comment:

Identified in a patient with optic atrophy, sensorineural hearing loss, and diabetes in published literature (PMID: 26875006); Not observed at significant frequency in large population cohorts (gnomAD); 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: 37041640, 33841295, 35469785, 25250959, 29447883, 34387732, 26875006, 21602428)

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
Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy.	Charif M	Frontiers in neurology	2021	PMID: 33841295
Whole exome sequencing identifies a pathogenic mutation in WFS1 in two large Chinese families with autosomal dominant all-frequency hearing loss and prenatal counseling.	Cheng H	International journal of pediatric otorhinolaryngology	2018	PMID: 29447883
Lamination of the Outer Plexiform Layer in Optic Atrophy Caused by Dominant WFS1 Mutations.	Majander A	Ophthalmology	2016	PMID: 26875006
Identification of a novel missense mutation in the WFS1 gene as a cause of autosomal dominant nonsyndromic sensorineural hearing loss in all-frequencies.	Bai X	American journal of medical genetics. Part A	2014	PMID: 25250959
Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype.	Rohayem J	Diabetes care	2011	PMID: 21602428

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_006005.3(WFS1):c.2390A>T (p.Asp797Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...