ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.2677G>A (p.Gly893Ser) (rs147336515)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000373836 SCV000411950 likely benign Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000260524 SCV000411951 likely benign Multiminicore Disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000334117 SCV000411952 likely benign Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000388593 SCV000411953 likely benign Myopathy, Central Core 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000427522 SCV000521244 likely benign not specified 2017-04-17 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.
Invitae RCV000537406 SCV000659897 likely benign RYR1-Related Disorders 2017-12-24 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000721467 SCV000852537 likely benign not provided 2017-10-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000427522 SCV000854893 likely benign not specified 2017-09-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000427522 SCV000918159 likely benign not specified 2019-08-23 criteria provided, single submitter clinical testing Variant summary: RYR1 c.2677G>A (p.Gly893Ser) results in a non-conservative amino acid change located in the first Ryr domain (IPR003032) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 277800 control chromosomes, predominantly at a frequency of 0.007 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2500 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Central Core Disease phenotype (2.8e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2677G>A has been reported in the literature in individuals affected with myopathy (Klein_2012, Maggi_2013, Isackson_2018), however one of these patient's unaffected father also tested positive for this variant, supporting a benign role for the variant (Klein_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CSER_CC_NCGL; University of Washington Medical Center RCV000148791 SCV000190529 likely benign Congenital myopathy 2014-06-01 no assertion criteria provided research

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