ClinVar Miner

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

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Total submissions: 9
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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 2021-01-05 criteria provided, single submitter clinical testing The p.Glu864Lys or c.2590G>A variant in WFS1 has been reported in ten probands with autosomal dominant hearing loss, including three families with Wolfram-like syndrome and one de novo proband. The variant segregated with disease in 15 affected individuals from eight families (Eiberg 2006 PMID: 16648378, Fukuoka 2007 PMID: 17492394, Valero 2008 PMID: 18544103, Brownstein 2011 PMID: 21917145, Moteki 2011 PMID: 26346818, Kobayashi 2018 PMID: 29529044, Guan 2020 PMID: 32567228, LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss. ACMG/AMP Criteria applied: PS2, PP1_Strong, PM2, PS4_Moderate, BP4.
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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000523215 SCV001249099 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Invitae RCV000523215 SCV001589182 pathogenic not provided 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 864 of the WFS1 protein (p.Glu864Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant Wolfram-like syndrome and nonsyndromic deafness (PMID: 16648378, 21917145, 29529044, 17492394). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4526). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004784 SCV000024960 pathogenic Wolfram-like syndrome, autosomal dominant 2008-06-01 no assertion criteria provided literature only
GeneReviews RCV000020637 SCV000041158 pathologic Autosomal dominant nonsyndromic deafness 6 2009-02-24 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000020637 SCV000044800 pathogenic Autosomal dominant nonsyndromic deafness 6 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 Autosomal dominant nonsyndromic deafness 6 2018-05-07 no assertion criteria provided research Dominant, postlingual, moderate-profound HL, U-shaped audiogram

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