ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.1453A>G (p.Met485Val) (rs147723844)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000210377 SCV000190553 uncertain significance Malignant hyperthermia 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Genetic Services Laboratory, University of Chicago RCV000119526 SCV000194808 uncertain significance not provided 2013-11-05 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148814 SCV000265684 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119526 SCV000337511 uncertain significance not provided 2015-11-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000056059 SCV000411886 likely benign Myopathy, Central Core 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000367231 SCV000411887 likely benign Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000276319 SCV000411888 likely benign Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000333715 SCV000411889 likely benign Multiminicore Disease 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000558155 SCV000659853 uncertain significance RYR1-Related Disorders 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 485 of the RYR1 protein (p.Met485Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs147723844, ExAC 0.07%). This variant has been reported in individuals with congenital myopathy. In one affected individual, this variant (p.M485V) occurred in cis with a second missense variant (p.R109W) on one allele, while a third missense variant (p.D708N) and a nonsense variant (p.R2241X) were present on the second allele (PMID: 23553787). Two additional individuals with congenital myopathy were found to carry this variant (p.M485V) along with two other RYR1 variants: in the first individual, the additional variants were c.325C>T (p.R109W) and c.4485G>A (p.Y1495*), and in the second individual, the additional variants were c.2122G>A (p.D708N) and c.6721C>T (p.R2241*) (PMID: 22473935). This variant has also been reported in cis with p.R109W in two individuals from one family affected with multiminicore myopathy (PMID: 16380615) and in two siblings affected with core myopathy and their unaffected father (PMID: 16940308). ClinVar contains an entry for this variant (Variation ID: 133076). Due to the multiple reported instances of this variant p.M485V along with the missense variant p.R109W in affected individuals, experimental studies have attempted to determine which variant, if either, affects the function of the RYR1 protein in vitro. In two separate publications, conflicting evidence on the effect of the p.M485V variant on RYR1 protein function has been presented. More convincing evidence is needed to determine the functional impact of the co-occurring p.R109W variant (PMID: 16940308, 18171678). This sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). In summary, this variant is present in the population and in affected individuals. Experimental evidence is not conclusive as to the role of this missense variant in protein function and disease. For these reasons, this variant has been classified as a Variant of Uncertain Significance.
GeneDx RCV000294840 SCV000730602 likely benign not specified 2018-03-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics,PreventionGenetics RCV000119526 SCV000852427 uncertain significance not provided 2016-12-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000119526 SCV000892250 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
GeneReviews RCV000056059 SCV000087120 non-pathogenic Myopathy, Central Core 2010-05-11 no assertion criteria provided curation Converted during submission to Benign.
Leiden Muscular Dystrophy (RYR1) RCV000119526 SCV000154433 not provided not provided no assertion provided not provided

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