ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2051C>T (p.Ala684Val) (rs387906930)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200668 SCV000252536 pathogenic not provided 2021-02-15 criteria provided, single submitter clinical testing Published functional studies of the A684V variant in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indication that the variant in disease-causing (Rendtorff et al., 2011); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28432734, 29529044, 21067485, 21538838, 11295831, 28468959, 12022290, 26435059, 22238590, 26875006, 30577886, 32567228, 33098801)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000200668 SCV000258031 pathogenic not provided 2015-02-05 criteria provided, single submitter clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000023514 SCV000680436 pathogenic Wolfram-like syndrome, autosomal dominant 2017-10-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000605882 SCV000731501 pathogenic Wolfram syndrome 1; Rare genetic deafness 2017-03-26 criteria provided, single submitter clinical testing The p.Ala684Val variant in WFS1 has been reported in 6 individuals with autosoma l dominant Wolfram-like syndrome (hearing loss and optic atrophy) and segregated in >10 affected family members across 4 different families (Rendtoff 2011, Maja nder 2016). In one of these families, a sib-pair presented with clinical feature s of autosomal recessive Wolfram syndrome (juvenile-onset diabetes mellitus, opt ic atrophy, bilateral profound sensorineural hearing loss from birth or infancy, and congenital cataracts), and were found to carry the p.Ala684Val in compound heterozygosity with a second WFS1 variant (p.Val415del). The p.Ala684Val variant was inherited from their father, who had Wolfram-like features, and the other v ariant was inherited from their mother who was unaffected (Mets 2010, Rendtoff 2 011). Two additional individuals with autosomal recessive Wolfram syndrome were reported with the p.Ala684Val variant, one of whom also had a second pathogenic variant in WFS1 (Tessa 2001, Aloi 2012). In addition, in vitro expression studie s suggest that the p.Ala684Val variant may impact normal expression of WFS1 (Ren dtorff 2011). Furthermore, this variant is reported in the ClinVar database as a pathogenic variant (Variation ID# 30556), and was absent in large population st udies. In summary, this variant meets criteria to be classified as pathogenic fo r both autosomal recessive Wolfram syndrome and autosomal dominant Wolfram-like syndrome based upon reported familial cases, absence from controls, and function al evidence.
Ambry Genetics RCV000623116 SCV000742873 pathogenic Inborn genetic diseases 2017-08-24 criteria provided, single submitter clinical testing
Eurofins NTD, LLC RCV000200668 SCV000862912 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000200668 SCV001146651 pathogenic not provided 2019-07-16 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease, and data include affected and unaffected individuals from multiple families.
Invitae RCV000200668 SCV001589181 pathogenic not provided 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 684 of the WFS1 protein (p.Ala684Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of autosomal dominant Wolfram-like syndrome (PMID: 21538838, 22238590, 29529044). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30556). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000023514 SCV001739301 pathogenic Wolfram-like syndrome, autosomal dominant 2019-09-13 criteria provided, single submitter clinical testing
OMIM RCV000023514 SCV000044805 pathogenic Wolfram-like syndrome, autosomal dominant 2011-06-01 no assertion criteria provided literature only
OMIM RCV000023515 SCV000044806 pathogenic Wolfram syndrome 1 2011-06-01 no assertion criteria provided literature only
Genomics England Pilot Project,Genomics England RCV001542531 SCV001760141 likely pathogenic Autosomal dominant nonsyndromic hearing loss 6 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000200668 SCV001807389 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000200668 SCV001917382 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000200668 SCV001951728 pathogenic not provided no assertion criteria provided clinical testing

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