ClinVar Miner

Submissions for variant NM_016373.4(WWOX):c.251C>G (p.Thr84Ser) (rs757145186)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489268 SCV000577481 uncertain significance not provided 2017-03-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the WWOX gene. The T84S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T84S 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 T84S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, 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 RCV000650199 SCV000772036 uncertain significance Epileptic encephalopathy, early infantile, 1; Spinocerebellar ataxia, autosomal recessive 12 2017-09-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 84 of the WWOX protein (p.Thr84Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs757145186, ExAC 0.003%). This variant has not been reported in the literature in individuals with WWOX-related disease. ClinVar contains an entry for this variant (Variation ID: 426908). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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