ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.10616G>A (p.Arg3539His) (rs143987857)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Human Development Section,National Institutes of Health RCV000209955 SCV000265737 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148796 SCV000190534 likely benign Myopathy, Central Core 2014-06-01 no assertion criteria provided research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000119414 SCV000575180 likely pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000203202 SCV000257708 uncertain significance not specified 2015-06-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119414 SCV000232393 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000119414 SCV000234974 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing The R3539H variant in the RYR1 gene has been reported previously in the heterozygous state, and opposite of another RYR1 variant, in individuals with core myopathies, and in other individuals with malignant hyperthermia (Monnier et al., 2008; Snoeck et al., 2015; Brandom et al., 2013; Klein et al., 2012; Voermans et al., 2013). The R3539H variant was also observed in unaffected individuals in control populations and in cohort studies (Brandom et al., 2013; Dorschner et al., 2013). The R3539H variant is observed in 384/126088 (0.30%) alleles from individuals of non-Finnish European background, including one homozygous individual in large population cohorts (Lek et al., 2016). The R3539H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R3539H as a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000203202 SCV000596887 uncertain significance not specified 2017-02-02 criteria provided, single submitter clinical testing
Invitae RCV000541657 SCV000659754 likely benign RYR1-Related Disorders 2018-01-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000203202 SCV000540251 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified in HGMD as DM relating to central core disease and is reported in 10 papers, with comments suggesting VUS/LB. This variant has a Max MAF of 0.30% in ExAC (384/126200 European chrs including 1 homozygote - high for central core disease prevalence of 6/100,000). It is classified in ClinVar as VUS by 4 submitters (Emory, GeneDx, CHOP, Biesecker), and Likely benign by U Wash.
Leiden Muscular Dystrophy (RYR1) RCV000119414 SCV000154321 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119414 SCV000852216 uncertain significance not provided 2016-05-25 criteria provided, single submitter clinical testing

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