ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.11608+2T>C

gnomAD frequency: 0.00001  dbSNP: rs1443083095
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000815205 SCV000955653 likely pathogenic RYR1-related disorder 2023-09-15 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 658385). 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. This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 23919265, 25960145, 28818389, 30611313).
All of Us Research Program, National Institutes of Health RCV004001773 SCV004840260 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-13 criteria provided, single submitter clinical testing This variant causes a T to C nucleotide substitution at the +2 position of intron 83 of the RYR1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 1/251080 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar variation ID: 658385). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
GeneDx RCV005092430 SCV005848426 likely pathogenic not provided 2024-08-12 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Has not been previously published as pathogenic or benign to our knowledge

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