VCV001328696.11 - ClinVar

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

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.

(4)

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.

Pathogenic/Likely pathogenic

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.2206G>A (p.Gly736Ser)

Variation ID: 1328696 Accession: VCV001328696.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.1 4: 6302001 (GRCh38) [ NCBI UCSC ] 4: 6303728 (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	Dec 25, 2021	Sep 16, 2024	Jun 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006005.3:c.2206G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005996.2:p.Gly736Ser	missense
NM_001145853.1:c.2206G>A	NP_001139325.1:p.Gly736Ser	missense
NC_000004.12:g.6302001G>A
NC_000004.11:g.6303728G>A
NG_011700.1:g.37152G>A
LRG_1417:g.37152G>A
LRG_1417t1:c.2206G>A	LRG_1417p1:p.Gly736Ser

... more HGVS ... less HGVS

Protein change

G736S

Other names

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

Canonical SPDI

NC_000004.12:6302000:G: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.

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

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

dbSNP: rs71532864 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	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 2, 2024	RCV001797328.11
Wolfram syndrome 1	Pathogenic (1)	criteria provided, single submitter	Aug 15, 2023	RCV003321872.1

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.
Pathogenic (Aug 21, 2022)	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: SCV002236433.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 8808601‚ 10521293‚ 32179840 Comment: 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 … (more) 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). (less)
Likely pathogenic (Jun 02, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002038782.3 First in ClinVar: Dec 25, 2021 Last updated: Sep 16, 2024	Comment: 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, … (more) 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) (less)
Pathogenic (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Wolfram syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Department Of Endocrinology, Sanjay Gandhi Postgraduate Institute Of Medical Sciences Accession: SCV004025931.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Publications: PubMed (4) PubMed: 10521293‚ 31264968‚ 15605410‚ 32179840 Comment: Missense variation in exon 8 of the WFS1 gene (chr4:g.6302001G>A) which replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, … (more) Missense variation in exon 8 of the WFS1 gene (chr4:g.6302001G>A) which replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 736 of the WFS1 protein (p.Gly736Ser). The observed variation has previously been reported in patients affected with Wolfram syndrome (PMID: 10521293, 31264968, 15605410, 32179840). This variant is present in population databases (rs71532864, gnomAD 0.006%). ClinVar contains an entry for this variant (Variation ID: 1328696). The in-silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. PS1, PM1, PM2, PM3, PM5, PP3. (less) Clinical Features: Diabetes mellitus (present) , Optic atrophy (absent) , Diabetes insipidus (absent) , Abnormal renal morphology (absent) , Sensorineural hearing loss disorder (absent) Age: 0-9 years Sex: male Ethnicity/Population group: Indian Geographic origin: India Comment on evidence: Patient presented with young onset, insulin requiring diabetes mellitus and was suspected to have type 1 diabetes mellitus. Genetic testing done since she was negative … (more) Patient presented with young onset, insulin requiring diabetes mellitus and was suspected to have type 1 diabetes mellitus. Genetic testing done since she was negative for all islet antibodies. (less) Method: DNA was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean depth of >80-100X on Illumina sequencing platform. We follow the GATK best practices framework for identification of germline variants in the sample using Sentieon [Sentieon]. The sequences obtained are aligned to human reference genome (GRCh38) using BWA aligner [Sentieon, PMID:20080505] and analyzed using Sentieon for removing duplicates, recalibration and re- alignment of indels [Sentieon]. Sentieon haplotype caller is then used to identify variants in the sample. The germline variants identified in the sample is deeply annotated using VariMAT pipeline. Gene annotation of the variants is performed using VEP program [PMID: 20562413] against the Ensembl release 99 human gene model [PMID: 29155950]. Testing laboratory: Medgenome labs private limited Date variant was reported to submitter: 2023-02-06 Testing laboratory interpretation: Likely pathogenic
Pathogenic (Aug 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	not provided Affected status: yes Allele origin: germline	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar Accession: SCV004100830.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 8808601‚ 10521293‚ 32179840‚ 28492532 Number of individuals with the variant: 2 Age: 20-30 years Sex: female Geographic origin: Tunisia

Comment:

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).

Comment:

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)

Comment:

Missense variation in exon 8 of the WFS1 gene (chr4:g.6302001G>A) which replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 736 of the WFS1 protein (p.Gly736Ser). The observed variation has previously been reported in patients affected with Wolfram syndrome (PMID: 10521293, 31264968, 15605410, 32179840). This variant is present in population databases (rs71532864, gnomAD 0.006%). ClinVar contains an entry for this variant (Variation ID: 1328696). The in-silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. PS1, PM1, PM2, PM3, PM5, PP3.

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
Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.	La Morgia C	Scientific reports	2020	PMID: 32179840
Residual β cell function and monogenic variants in long-duration type 1 diabetes patients.	Yu MG	The Journal of clinical investigation	2019	PMID: 31264968
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.	Nykamp K	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28492532
Wolfram syndrome in French population: characterization of novel mutations and polymorphisms in the WFS1 gene.	Giuliano F	Human mutation	2005	PMID: 15605410
Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1.	Hardy C	American journal of human genetics	1999	PMID: 10521293
Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity.	Collier DA	American journal of human genetics	1996	PMID: 8808601

Text-mined citations for rs71532864 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs71532864 ...