ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.3424del (p.Trp1142fs)

gnomAD frequency: 0.00001  dbSNP: rs1168352165
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001975195 SCV002240230 pathogenic RYR1-related disorder 2021-02-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1142Glyfs*10) 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: 20583297, 20839240, 23919265, 28818389). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR1-related conditions. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV003514536 SCV004358055 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-21 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 26 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. To our knowledge, this variant has not been reported in individuals affected with malignant hyperthermia in the literature. This variant has been identified in 1/251462 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) (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
All of Us Research Program, National Institutes of Health RCV003514536 SCV004820810 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-10-02 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 26 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. To our knowledge, this variant has not been reported in individuals affected with malignant hyperthermia in the literature. This variant has been identified in 1/251462 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. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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