ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.12629A>G (p.Lys4210Arg) (rs138932463)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079123 SCV000110992 uncertain significance not provided 2013-09-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764198 SCV000895201 uncertain significance Myopathy, Central Core; Malignant hyperthermia, susceptibility to, 1; Minicore myopathy; Congenital myopathy with fiber type disproportion 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000534293 SCV000659794 uncertain significance RYR1-Related Disorders 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 4210 of the RYR1 protein (p.Lys4210Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs138932463, ExAC 0.05%). This variant has been reported in combination with another RYR1 variant in an individual affected with multiminicore disease (MmD) (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 93246). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This sequence change is located in the C-terminal mutational hotspot of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). 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.

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