ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14678G>A (p.Arg4893Gln)

dbSNP: rs118192151
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel,ClinGen RCV001588887 SCV001815847 uncertain significance Malignant hyperthermia of anesthesia 2021-11-10 reviewed by expert panel curation This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with glutamine at codon 4893 of the RYR1 protein, p.(Arg4893Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction (PMID:30236257, UK (Leeds) MH Investigational Unit). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.963) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PM1_Supporting, PP3_Moderate.
GeneDx RCV000119546 SCV000582675 pathogenic not provided 2018-07-25 criteria provided, single submitter clinical testing The R4893Q pathogenic variant in the RYR1 gene has been reported previously in multiple unrelated families with central core disease, in association with autosomal dominant inheritance (Davis et al., 2003). Functional studies demostrated that R4893Q reduces calcium release and dramatically alters protein function (Kraeva et al., 2013). The R4893Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R4893Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position that is predicted to be located within the pore forming domain. Therefore, we interpret R4893Q as a pathogenic variant.
Genetic Services Laboratory,University of Chicago RCV000119546 SCV000596909 likely pathogenic not provided 2016-03-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000119546 SCV000852448 pathogenic not provided 2016-10-14 criteria provided, single submitter clinical testing
Invitae RCV001218792 SCV001390695 pathogenic RYR1-Related Disorders 2021-11-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4893 of the RYR1 protein (p.Arg4893Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia and central core disease (CCD) (PMID: 12565913, 22550088, 23183335, 25628744, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65988). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 23183335). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg4893 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11709545, 14670767). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001218792 SCV002500623 pathogenic RYR1-Related Disorders 2022-03-24 criteria provided, single submitter clinical testing Variant summary: RYR1 c.14678G>A (p.Arg4893Gln) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 282656 control chromosomes (gnomAD and publication data). c.14678G>A has been reported in the literature in multiple individuals affected with Central Core Disease and Malignant Hyperthermia Susceptibility (e.g. Davis_2003, Chang_2013, Kraeva_2013, Jung_2015, Miller_2018). In addition, this variant was co-segregated with disease in at least two unrelative families (Chang_2013, Miller_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function showed that equivalent mutations in rabbit RYR1 has equivalent Ca2+ signaling activity as an RYR1 null control in a cell transfection assay (Kraeva_2013) and showed 60% reduction in voltage sensitivity when assayed via electrophysiology (Kraeva_2013). Different missense substitutions at this codon (R4893P, R4893W) were reported in individuals affected with Central core disease in HGMD database (PMID: 16621918, 11709545). This suggests that the arginine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic (R4893P and R4893W have been classified as pathogenic in ClinVar database). Six ClinVar submitters, including one expert panel, has assessed the variant since 2014: the variant was classified as of uncertain significance by the expert panel, as likely pathogenic by one laboratory, and pathogenic by four laboratories. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000056235 SCV000087324 pathologic Central core myopathy 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119546 SCV000154453 not provided not provided no assertion provided not provided
PerkinElmer Genomics RCV000119546 SCV002019969 pathogenic not provided 2019-09-04 no assertion criteria provided clinical testing

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