ClinVar Miner

Submissions for variant NM_016373.4(WWOX):c.713A>G (p.Tyr238Cys) (rs142806268)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000442070 SCV000511459 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
GeneDx RCV000442070 SCV000571828 uncertain significance not provided 2017-08-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the WWOX gene. The Y238C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y238C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y238C 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. Additionally, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000650207 SCV000772044 uncertain significance Epileptic encephalopathy, early infantile, 1; Spinocerebellar ataxia, autosomal recessive 12 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 238 of the WWOX protein (p.Tyr238Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs142806268, ExAC 0.1%). This variant has not been reported in the literature in individuals with WWOX-related disease. ClinVar contains an entry for this variant (Variation ID: 377189). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class 0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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