ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14130-2A>G

gnomAD frequency: 0.00001  dbSNP: rs1457662393
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001941795 SCV002230076 pathogenic RYR1-related disorder 2023-09-29 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 96 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 24961629). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1454292). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002497871 SCV002807268 pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2021-11-12 criteria provided, single submitter clinical testing
GeneDx RCV003325593 SCV004032011 pathogenic not provided 2023-03-07 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24961629, 29096039)
All of Us Research Program, National Institutes of Health RCV004010985 SCV004816689 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-04-03 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 96 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 autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar Variation ID: 1454292). Loss of RYR1 function due to haploinsufficiency is not an established disease mechanism for autosomal dominant malignant hyperthermia. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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