ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.6274+1G>A (rs1226228092)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000525713 SCV000659985 likely pathogenic RYR1-Related Disorders 2020-08-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 38 of the RYR1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR1-related conditions. 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 RYR1 are known to be pathogenic (PMID: 20583297, 20839240, 23919265, 28818389). 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.
PreventionGenetics,PreventionGenetics RCV000721603 SCV000852700 pathogenic not provided 2016-08-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000721603 SCV000857369 pathogenic not provided 2017-10-06 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853333 SCV000996192 likely pathogenic Multiminicore Disease 2018-08-28 criteria provided, single submitter clinical testing This variant affects the canonical splice donor site of intron 38 and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has not been reported in the medical literature to our knowledge. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/265694) and thus is presumed to be rare. Based on the available evidence, the c.6274+1G>A variant is classified as likely pathogenic.
GeneDx RCV000721603 SCV001795380 likely pathogenic not provided 2020-08-17 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Has not been previously published as pathogenic or benign to our knowledge; Deletions involving coding exons of this gene are a known mechanism of disease (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016)

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