ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10768G>A (p.Glu3590Lys)

gnomAD frequency: 0.00001  dbSNP: rs746611627
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721210 SCV000852223 uncertain significance not provided 2016-01-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000813223 SCV000953570 uncertain significance RYR1-related disorder 2022-07-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3590 of the RYR1 protein (p.Glu3590Lys). This variant is present in population databases (rs746611627, gnomAD 0.2%). 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: 590372). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
AiLife Diagnostics, AiLife Diagnostics RCV000721210 SCV002503293 uncertain significance not provided 2020-05-08 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000721210 SCV003810478 uncertain significance not provided 2019-06-26 criteria provided, single submitter clinical testing
GeneDx RCV000721210 SCV004035486 uncertain significance not provided 2023-03-10 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
All of Us Research Program, National Institutes of Health RCV003999810 SCV004820986 likely benign Malignant hyperthermia, susceptibility to, 1 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 3590 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia in the literature. This variant has been identified in 36/282594 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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