ClinVar Miner

Submissions for variant NM_016373.4(WWOX):c.605+5G>A (rs1039151413)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850619 SCV000992852 uncertain significance Spinocerebellar ataxia, autosomal recessive 12; Epileptic encephalopathy, early infantile, 28 2017-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000522383 SCV000619192 likely pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing The c.605+5 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.605+5 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.605+5 G>A destroys the natural donor site of intron 6 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000703936 SCV000832864 uncertain significance Epileptic encephalopathy, early infantile, 1; Spinocerebellar ataxia, autosomal recessive 12 2018-04-20 criteria provided, single submitter clinical testing This sequence change falls in intron 6 of the WWOX gene. It does not directly change the encoded amino acid sequence of the WWOX protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with WWOX-related disease. ClinVar contains an entry for this variant (Variation ID: 450592). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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