ClinVar Miner

Submissions for variant NM_016373.4(WWOX):c.673C>G (p.Leu225Val) (rs376040091)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522388 SCV000620188 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 L225V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L225V 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). This substitution occurs at a position that is conserved across species. However, the L225V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is 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 RCV000824069 SCV000964950 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 leucine with valine at codon 225 of the WWOX protein (p.Leu225Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs376040091, ExAC 0.04%). This variant has not been reported in the literature in individuals with WWOX-related disease. ClinVar contains an entry for this variant (Variation ID: 451480). 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: Not Available; PolyPhen-2: "Benign"; Align-GVGD: Not Available). 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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