ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.226-2dup (rs774388631)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000346879 SCV000329596 pathogenic not provided 2016-08-03 criteria provided, single submitter clinical testing The c.226-2dupA variant in the SYNE1 gene has been reported previously in one patient with adult-onset ataxia and progressive myoclonus epilepsy who was also heterozygous for a missense variant in the SYNE1 gene. However, the missense variant is classified as likely benign at GeneDx, and this individual was found to harbor a pathogenic variant in the PRNP gene that was thought to explain her clinical symptoms (Muona et al., 2015). This splice site variant destroys the canonical splice acceptor site in intron 4. It is predicted to cause abnormal gene splicing resulting in an in-frame protein product with an abnormal message. The c.226-2dupA variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.226-2dupA as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000346879 SCV000343022 uncertain significance not provided 2016-07-14 criteria provided, single submitter clinical testing
Invitae RCV001059448 SCV001224072 uncertain significance Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2019-07-09 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the SYNE1 gene. It does not directly change the encoded amino acid sequence of the SYNE1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs774388631, ExAC 0.02%). This variant has not been reported in the literature in individuals with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 279936). 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.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001270391 SCV001450674 likely pathogenic Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant; Arthrogryposis multiplex congenita 3, myogenic type 2020-03-23 no assertion criteria provided clinical testing

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