ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13673G>A (p.Arg4558Gln) (rs118192130)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000056231 SCV000190567 uncertain significance Myopathy, Central Core 2014-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119483 SCV000703968 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing
GeneReviews RCV000056231 SCV000087320 pathologic Myopathy, Central Core 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000119483 SCV000194806 likely pathogenic not provided 2014-03-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000056231 SCV000915830 likely pathogenic Myopathy, Central Core 2019-01-10 criteria provided, single submitter clinical testing The RYR1 c.13673G>A (p.Arg4558Gln) variant has been reported in three studies in which it was found in a compound heterozygous state in a total of five probands with central core disease from three families (Kossugue et al. 2007; Monnier et al. 2008; Remiche et al. 2015). In two of the families, the heterozygous parent of the probands was shown to be unaffected, and in one family, the heterozygous sibling was also unaffected (Kossugue et al. 2007; Remiche et al. 2015). The p.Arg4558Gln variant was absent from 200 control chromosomes and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. However, this frequency is based on one allele only, suggesting the variant is rare. Western blotting revealed reduced RYR1 protein expression in the muscle tissue of one proband (Monnier et al. 2008). The amino acid residue affected by the p.Arg4558Gln variant is evolutionarily conserved and is located in the M5 transmembrane fragment of the calcium channel. Based on the collective evidence, the p.Arg4558Gln variant is classified as likely pathogenic for pathogenicity for central core disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000685437 SCV000812918 likely pathogenic RYR1-Related Disorders 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 4558 of the RYR1 protein (p.Arg4558Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs118192130, ExAC 0.01%). This variant has been observed in combination with another RYR1 variant in several individuals affected with autosomal recessive central core disease, and has been observed to segregate with disease in affected families (PMID: 17226826, 18253926, 25747005). ClinVar contains an entry for this variant (Variation ID: 65984). 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119483 SCV000154390 not provided not provided no assertion provided not provided

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