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NM_006005.3(WFS1):c.1917G>A (p.Trp639Ter) AND Wolfram syndrome 1

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 23, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002286558.1

Allele description [Variation Report for NM_006005.3(WFS1):c.1917G>A (p.Trp639Ter)]

NM_006005.3(WFS1):c.1917G>A (p.Trp639Ter)

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.1917G>A (p.Trp639Ter)
HGVS:
  • NC_000004.12:g.6301712G>A
  • NG_011700.1:g.36863G>A
  • NM_001145853.1:c.1917G>A
  • NM_006005.3:c.1917G>AMANE SELECT
  • NP_001139325.1:p.Trp639Ter
  • NP_005996.1:p.Trp639Ter
  • NP_005996.2:p.Trp639Ter
  • LRG_1417t1:c.1917G>A
  • LRG_1417:g.36863G>A
  • LRG_1417p1:p.Trp639Ter
  • NC_000004.11:g.6303439G>A
  • NM_006005.2:c.1917G>A
Protein change:
W639*
Molecular consequence:
  • NM_001145853.1:c.1917G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_006005.3:c.1917G>A - nonsense - [Sequence Ontology: SO:0001587]
Functional consequence:
protein truncation [Variation Ontology: 0015]
Observations:
1

Condition(s)

Name:
Wolfram syndrome 1 (WFS1)
Identifiers:
MONDO: MONDO:0009101; MedGen: C4551693; Orphanet: 3463; OMIM: 222300

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002574772Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Aug 23, 2022) 		unknownclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
South Indian Muslimunknownyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences, SCV002574772.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1South Indian Muslim1not providednot providedclinical testing PubMed (1)

Description

The stop gained NM_006005.3(WFS1):c.1917G>A (p.Trp639Ter) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Trp639Ter variant is novel (not in any individuals) in 1kG All. The p.Trp639Ter variant is novel (not in any individuals) in gnomAD. This variant is predicted to cause loss of normal protein function through protein truncation. There are 23 downstream pathogenic loss of function variants, with the furthest variant being 249 residues downstream of this variant. This indicates that the region is critical to protein function. The p.Trp639Ter variant is a loss of function variant in the gene WFS1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_005996.2:p.N4Qfs*52 and 38 others. For these reasons, this variant has been classified as Likely Pathogenic.

Description

The p.Trp639Ter variant in WFS1 has been observed in homozygous state in two affected siblings with clinically suspected Wolfram syndrome ( the siblings had young onset diabetes mellitus, optic atrophy and sensorineural hearing loss) which is an autosomal recessive disorder. The variant is novel (not observed in any individuals in 1KG, gnomAD and our inhouse database). The variant is predicted to cause loss of normal protein function through protein truncation. There are 23 downstream pathogenic loss of function variants, with the furthest variant being 249 residues downstream of this variant. This indicates that the region is critical to protein function. The p.Trp639Ter variant is a loss of function variant in the gene WFS1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_005996.2:p.N4Qfs*52 and 38 others. For these reasons, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Dec 3, 2022