ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2590G>A (p.Glu864Lys) (rs74315205)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000599631 SCV000202081 pathogenic Rare genetic deafness 2013-08-14 criteria provided, single submitter clinical testing The p.Glu864Lys variant in WFS1 has been reported in five families with autosoma l dominant non-syndromic low frequency and mid-frequency hearing loss (ADNSHL), including two families with Wolfram-like syndrome. The variant was detected in t he heterozygous state and segregated with the ADNSHL or Wolfram-like syndrome ac ross 12 meioses, and it was not detected in control chromosomes (Eiberg 2006, Fu kuoka 2007, Valero 2008, Brownstein 2011). This variant was also not identified in large population studies. In addition, the glutamic acid (Glu) residue at pos ition 864 is highly conserved through vertebrate species. In summary, this varia nt meets our criteria to be classified as pathogenic for autosomal dominant hear ing loss primarily based upon segregation studies as well as supporting evidence from absence in controls and amino acid conservation.
GeneDx RCV000523215 SCV000617493 likely pathogenic not provided 2017-07-21 criteria provided, single submitter clinical testing The E864K variant in the WFS1 gene has been reported previously in the heterozygous state in association with autosomal dominant optic atrophy combined with hearing impairment and nonsyndromic low-frequency hearing impairment (Eiberg et al., 2006; Fukuoka et al., 2007; Valero et al., 2008). The E864K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E864K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E864K as a likely pathogenic variant.
OMIM RCV000004784 SCV000024960 pathogenic Wolfram-like syndrome, autosomal dominant 2008-06-01 no assertion criteria provided literature only
GeneReviews RCV000020637 SCV000041158 pathologic WFS1-Related Disorders 2009-02-24 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000020637 SCV000044800 pathogenic WFS1-Related Disorders 2008-06-01 no assertion criteria provided literature only
Laboratory of Prof. Karen Avraham,Tel Aviv University RCV000225037 SCV000282007 pathogenic DFNA6/14/38 Nonsyndromic Low-Frequency Sensorineural Hearing Loss 2016-02-19 no assertion criteria provided research Comgenital, low-tone, U-shaped HL
Laboratory of Prof. Karen Avraham,Tel Aviv University RCV000020637 SCV001164300 pathogenic WFS1-Related Disorders 2018-05-07 no assertion criteria provided research Dominant, postlingual, moderate-profound HL, U-shaped audiogram

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