ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.6838G>A (p.Val2280Ile) (rs193922797)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185536 SCV000238413 likely pathogenic Malignant hyperthermia, susceptibility to, 1 2014-07-17 no assertion criteria provided research This test identified one heterozygous variant (c.6838G>A;p.Val2280Ile) in the RYR1 gene (see Table IIIA). Variants in this gene have been associated with increased risk of malignant hyperthermia (autosomal dominant) and different types of congenital myopathies - central core disease (autosomal dominant or autosomal recessive), multiminicore disease (autosomal recessive), congenital fiber type disproportion (autosomal dominant or autosomal recessive). The RYR1 gene encodes for calcium channels that play a critical role in the movement of skeletal muscles. Risk for malignant hyperthermia is predominantly associated with the use of general anesthesia with specific anesthetics, which can trigger an episode (hypermetabolism, rhabdomyolysis, hyperkalaemia, cardiac arrhythmia). A very small number of individuals with malignant hyperthermia susceptibility appear to be at risk for heat stroke or exercise-induced rhabdomyolysis,). Malignant hyperthermia has been reported to occur in individuals without anesthetic exposure. If an episode is untreated, it can be life threatening. Alternative anesthetic treatments are available for known individuals susceptible to malignant hyperthermia. This variant has been reported in a family susceptible to malignant hyperthermia based on biochemical testing (Galli et al 2002,PMID: 12208234; Galli et al. 2006, PMID: 16835904), and computational evidence is also suggestive of this variant being a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000502398 SCV000596904 uncertain significance not specified 2017-02-02 criteria provided, single submitter clinical testing
Invitae RCV000691232 SCV000818981 uncertain significance RYR1-Related Disorders 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2280 of the RYR1 protein (p.Val2280Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs193922797, ExAC 0.02%). This variant has been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 12208234). ClinVar contains an entry for this variant (Variation ID: 133172). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16917943, 12565913, 23919265). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. 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.
Leiden Muscular Dystrophy (RYR1) RCV000119670 SCV000154577 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119670 SCV000852733 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing

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