ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14581C>T (p.Arg4861Cys) (rs118192181)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000119532 SCV000329691 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing The R4861C missense variant in the RYR1 gene has been reported multiple times in association with autosomal dominant central core disease (Davis et al., 2003; Bharucha-Goebel et al., 2013; RYR1 LOVD). Additionally, muscle histology identified central cores in affected individuals (Davis et al., 2003; Bharucha-Goebel et al., 2013). The R4861C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R4861C variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants at the same position (R4861H) and in nearby residues (A4856G, N4858D, F4860V, Y4864H/C) have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, R4861C is considered a pathogenic variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000119532 SCV000510708 pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing
Invitae RCV000695782 SCV000824302 pathogenic RYR1-Related Disorders 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 4861 of the RYR1 protein (p.Arg4861Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in several individuals affected with central core disease (CCD) (PMID: 17483490, 25960145, 26684984) and in several individuals affected with CCD or neonatal onset myopathy (PMID: 12565913, 23553484). ClinVar contains an entry for this variant (Variation ID: 65986). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg4861His) has been determined to be pathogenic (PMID: 16621918, 12565913, 25521991, 11709545, 23394784). This suggests that the arginine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense pathogenic variants are found (PMID: 16084090). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000119532 SCV000852432 pathogenic not provided 2016-09-22 criteria provided, single submitter clinical testing
GeneReviews RCV000056233 SCV000087322 pathologic Central core myopathy 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119532 SCV000154439 not provided not provided no assertion provided not provided

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