ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.1440+2T>G

dbSNP: rs1555767403
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598890 SCV000710039 pathogenic not provided 2019-05-22 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31618753)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258222 SCV001435118 uncertain significance Malignant hyperthermia, susceptibility to, 1 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV002289892 SCV002580298 likely pathogenic Central core myopathy 2021-07-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003591756 SCV004303985 likely pathogenic RYR1-related disorder 2022-11-29 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 503752). Disruption of this splice site has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 31618753). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 13 of the RYR1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
All of Us Research Program, National Institutes of Health RCV001258222 SCV004822570 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-08-15 criteria provided, single submitter clinical testing

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