ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.11608+1G>C

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003088588 SCV003485595 likely pathogenic RYR1-related disorder 2022-10-26 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. This sequence change affects a donor splice site in intron 83 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected 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.
All of Us Research Program, National Institutes of Health RCV004804560 SCV005425310 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-07-20 criteria provided, single submitter clinical testing This variant causes a G>C nucleotide substitution at the +1 position of intron 83 in the RYR1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar Variation ID: 2170374). Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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