NM_006005.3(WFS1):c.2486T>C (p.Leu829Pro) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 2, 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:: RCV000726781.11

Allele description [Variation Report for NM_006005.3(WFS1):c.2486T>C (p.Leu829Pro)]

NM_006005.3(WFS1):c.2486T>C (p.Leu829Pro)

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.2486T>C (p.Leu829Pro)

HGVS:

NC_000004.12:g.6302281T>C
NG_011700.1:g.37432T>C
NM_001145853.1:c.2486T>C
NM_006005.3:c.2486T>CMANE SELECT
NP_001139325.1:p.Leu829Pro
NP_005996.2:p.Leu829Pro
LRG_1417t1:c.2486T>C
LRG_1417:g.37432T>C
LRG_1417p1:p.Leu829Pro
NC_000004.11:g.6304008T>C
O76024:p.Leu829Pro

Protein change:

L829P; LEU829PRO

Links:

UniProtKB: O76024#VAR_032967; OMIM: 606201.0015; dbSNP: rs104893883

NCBI 1000 Genomes Browser:

rs104893883

Molecular consequence:

NM_001145853.1:c.2486T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006005.3:c.2486T>C - 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
SCV000702983	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Nov 2, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002307708	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11709537, 17492394, 31363008, 28492532
SCV003923376	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 2, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000702983

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Likely pathogenic
(Nov 2, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV002307708

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003923376

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 2, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss.

Bespalova IN, Van Camp G, Bom SJ, Brown DJ, Cryns K, DeWan AT, Erson AE, Flothmann K, Kunst HP, Kurnool P, Sivakumaran TA, Cremers CW, Leal SM, Burmeister M, Lesperance MM.

Hum Mol Genet. 2001 Oct 15;10(22):2501-8.

PubMed [citation]

PMID:: 11709537
PMCID:: PMC6198816

Mutations in the WFS1 gene are a frequent cause of autosomal dominant nonsyndromic low-frequency hearing loss in Japanese.

Fukuoka H, Kanda Y, Ohta S, Usami SI.

J Hum Genet. 2007;52(6):510-515. doi: 10.1007/s10038-007-0144-3. Epub 2007 May 11.

PubMed [citation]

PMID:: 17492394

See all PubMed Citations (4)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000702983.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	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		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002307708.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 829 of the WFS1 protein (p.Leu829Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant deafness or clinical features of autosomal recessive Wolfram syndrome (PMID: 11709537, 17492394, 31363008). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4521). 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. For these reasons, this variant has been classified as Pathogenic.

#	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 GeneDx, SCV003923376.2

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

Description

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: 12650912, 20738327, 12955714, 12707188, 12707187, 18776598, 17492394, 19877185, 12181639, 31363008, 11709537, 37121227, 36225977, Zhao2023[paper])

#	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: Oct 26, 2024

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