ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.12624+2dup

gnomAD frequency: 0.00003  dbSNP: rs772165973
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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 RCV003592818 SCV004272431 uncertain significance RYR1-related disorder 2024-01-09 criteria provided, single submitter clinical testing This sequence change falls in intron 90 of the RYR1 gene. It does not directly change the encoded amino acid sequence of the RYR1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs772165973, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV004804621 SCV005425360 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-08-13 criteria provided, single submitter clinical testing This variant causes the duplication of one nucleotide at the +2 position of intron 90 in 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 3/272556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to haploinsufficiency is associated with congenital myopathy (https://clinicalgenome.org/), but it is not an established disease mechanism for autosomal dominant malignant hyperthermia susceptibility. Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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