ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.13525_13531dup (p.Lys4511fs)

gnomAD frequency: 0.00001  dbSNP: rs928989953
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657362 SCV000779094 likely pathogenic not provided 2019-10-18 criteria provided, single submitter clinical testing Frameshift variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Reported in an individual with central core disease who also carried a second pathogenic variant in RYR1 (Snoeck et al., 2015); This variant is associated with the following publications: (PMID: 25960145)
Labcorp Genetics (formerly Invitae), Labcorp RCV001383438 SCV001582585 pathogenic RYR1-related disorder 2023-04-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 545809). This premature translational stop signal has been observed in individual(s) with central core disease (PMID: 25960145). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys4511Argfs*74) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313).
Revvity Omics, Revvity RCV000657362 SCV002019922 pathogenic not provided 2020-03-09 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477470 SCV002791577 likely pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2021-12-07 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004004184 SCV004816238 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-10-02 criteria provided, single submitter clinical testing This variant inserts 7 nucleotides in exon 93 of the RYR1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to haploinsufficiency is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotypes (ClinVar Variation ID: 545809, PMID: 25960145). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV004556808 SCV005045787 likely pathogenic Congenital multicore myopathy with external ophthalmoplegia 2023-11-13 criteria provided, single submitter clinical testing

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