ClinVar Miner

Submissions for variant NM_004287.3(GOSR2):c.336+1G>A (rs141554661)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000194518 SCV000247491 pathogenic Epilepsy, progressive myoclonic 6 2015-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000439078 SCV000516279 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing The c.336+1 G>A splice site variant in the GOSR2 gene has been reported previously in an individual with congenital muscular dystrophy and myoclonic epilepsy who was compound heterozygous for c.336+1 G>A and another GOSR2 pathogenic variant (Tsai et al, 2013). This variant destroys the canonical splice donor site in intron 4. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.336+1 G>A variant is observed in 29/125982 (0.02%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016). Therefore, c.336+1 G>A is considered a pathogenic variant.
Invitae RCV000703812 SCV000832731 likely pathogenic Progressive myoclonic epilepsy 2018-10-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the GOSR2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs141554661, ExAC 0.01%). This variant has not been reported in the literature in individuals with GOSR2-related disease. ClinVar contains an entry for this variant (Variation ID: 211092). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GOSR2 are known to be pathogenic (PMID: 21549339). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000720674 SCV000851553 likely pathogenic Seizures 2017-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without splicing assay data in support of pathogenicity,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species

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