NM_006005.3(WFS1):c.1243_1245del (p.Val415del) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 13, 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:: RCV000199829.10

Allele description [Variation Report for NM_006005.3(WFS1):c.1243_1245del (p.Val415del)]

NM_006005.3(WFS1):c.1243_1245del (p.Val415del)

Gene:

WFS1:wolframin ER transmembrane glycoprotein [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

4p16.1

Genomic location:

Preferred name:

NM_006005.3(WFS1):c.1243_1245del (p.Val415del)

Other names:

WFS1, 3-BP DEL, VAL415DEL

HGVS:

NC_000004.11:g.6302763_6302765del
NC_000004.12:g.6301038_6301040del
NG_011700.1:g.36189_36191del
NM_001145853.1:c.1243_1245del
NM_006005.3:c.1243_1245delMANE SELECT
NP_001139325.1:p.Val415del
NP_005996.2:p.Val415del
LRG_1417t1:c.1243_1245del
LRG_1417:g.36189_36191del
LRG_1417p1:p.Val415del
NC_000004.11:g.6302763_6302765del
NC_000004.11:g.6302765_6302767del
NC_000004.11:g.6302765_6302767delGTC
NM_006005.3:c.1243_1245del
NM_006005.3:c.1243_1245delGTCMANE SELECT
p.V415del

Protein change:

V415del; VAL415DEL

Links:

OMIM: 606201.0029; dbSNP: rs863224265

NCBI 1000 Genomes Browser:

rs863224265

Molecular consequence:

NM_001145853.1:c.1243_1245del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_006005.3:c.1243_1245del - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV000252550	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 11, 2022)	germline	clinical testing	Citation Link,
SCV002217148	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10521293, 21067485, 27617222, 31600780, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000252550

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 11, 2022)

germline

clinical testing

Citation Link,

SCV002217148

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 13, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1.

Hardy C, Khanim F, Torres R, Scott-Brown M, Seller A, Poulton J, Collier D, Kirk J, Polymeropoulos M, Latif F, Barrett T.

Am J Hum Genet. 1999 Nov;65(5):1279-90.

PubMed [citation]

PMID:: 10521293
PMCID:: PMC1288280

Congenital cataracts in two siblings with Wolfram syndrome.

Mets RB, Emery SB, Lesperance MM, Mets MB.

Ophthalmic Genet. 2010 Dec;31(4):227-9. doi: 10.3109/13816810.2010.516056.

PubMed [citation]

PMID:: 21067485

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000252550.8

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

Description

Published functional studies demonstrate a damaging effect resulting in decreased wolframin expression compared to the wildtype (Rendtorff et al., 2011); In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21067485, 28432734, 16151413, 21446023, 15277431, 18806274, 21538838, 10521293, 21602428, 8808601, 27617222, 19042979, 23429432, 31600780)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002217148.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant, c.1243_1245del, results in the deletion of 1 amino acid(s) of the WFS1 protein (p.Val415del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750767821, gnomAD 0.03%). This variant has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 10521293, 21067485, 27617222, 31600780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215406). 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

Last Updated: Nov 3, 2024

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