ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13934G>A (p.Arg4645Gln) (rs193922860)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454682 SCV000540257 uncertain significance not specified 2016-12-21 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 1 paper in HGMD in an unspecified number of malignant hyperthermia patients (classified as DM). This variant is present in ClinVar with no interpretation. The variant has a Max MAF of 0.03% in ExAC (3 East Asian alleles) and 0.04% in gnomAD (7 East Asian alleles). 3 non-mammals have a Gln at this position.
Invitae RCV000525051 SCV000659836 uncertain significance RYR1-Related Disorders 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 4645 of the RYR1 protein (p.Arg4645Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs193922860, ExAC 0.03%). This variant has been reported in individuals affected with malignant hyperthermia (PMID: 16732084, 16917943) and in an individual with suspected neuroleptic malignant syndrome (PMID: 19931341). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. In summary, this variant is a rare missense change with uncertain impact on protein function and mRNA splicing. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics,PreventionGenetics RCV000119491 SCV000852379 pathogenic not provided 2013-11-22 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (RYR1) RCV000119491 SCV000154398 not provided not provided no assertion provided not provided

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