ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.1559T>C (p.Leu520Pro)

gnomAD frequency: 0.00001  dbSNP: rs1384515505
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721418 SCV000852480 uncertain significance not provided 2013-10-18 criteria provided, single submitter clinical testing
GeneDx RCV000721418 SCV002064129 likely pathogenic not provided 2024-04-29 criteria provided, single submitter clinical testing Reported in associated with a RYR1-associated disorder, however no specific information was provided (PMID: 32236737); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33767344, 32236737)
Labcorp Genetics (formerly Invitae), Labcorp RCV002535002 SCV003269837 uncertain significance RYR1-related disorder 2022-07-08 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 520 of the RYR1 protein (p.Leu520Pro). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 590483). 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 expected to disrupt RYR1 protein function. 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 RCV003999828 SCV004820748 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-07-10 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 520 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotypes (ClinVar Variation ID: 590483). This variant has been identified in 2/251494 chromosomes 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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