ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.5273C>T (p.Pro1758Leu)

gnomAD frequency: 0.00001  dbSNP: rs371317448
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001298329 SCV001487381 uncertain significance RYR1-related disorder 2023-04-24 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 1001968). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is present in population databases (rs371317448, gnomAD 0.008%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1758 of the RYR1 protein (p.Pro1758Leu).
Fulgent Genetics, Fulgent Genetics RCV002493572 SCV002780473 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2021-12-20 criteria provided, single submitter clinical testing
GeneDx RCV003322877 SCV004028285 uncertain significance not provided 2023-02-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
All of Us Research Program, National Institutes of Health RCV004004977 SCV004822931 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 1758 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 3/276506 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

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