ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7072A>C (p.Ile2358Leu)

gnomAD frequency: 0.00001  dbSNP: rs759306349
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721637 SCV000852749 uncertain significance not provided 2017-10-20 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000721637 SCV002770438 uncertain significance not provided 2022-06-22 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002485827 SCV002777524 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 2021-09-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002535010 SCV003461854 uncertain significance RYR1-related disorder 2021-09-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 2358 of the RYR1 protein (p.Ile2358Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs759306349, ExAC 0.003%). This variant has been observed in individual(s) with clinical features of malignant hyperthermia (PMID: 23558838). ClinVar contains an entry for this variant (Variation ID: 590581). 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.
All of Us Research Program, National Institutes of Health RCV003999857 SCV004820899 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with leucine at codon 2358 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with malignant hyperthermia susceptibility (PMID: 23558838, 31559918). This variant has been identified in 1/239514 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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