ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14270G>A (p.Arg4757His) (rs768360593)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000721359 SCV000339056 uncertain significance not provided 2016-01-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000293888 SCV000413016 uncertain significance Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000351106 SCV000413017 uncertain significance Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000389289 SCV000413018 uncertain significance Multiminicore Disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000287938 SCV000413019 uncertain significance Myopathy, Central Core 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000721359 SCV000576933 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing The R4757H variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R4757H variant is observed in 18/111538 (0.016%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The R4757H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R4757H as a variant of uncertain significance.
Invitae RCV000539271 SCV000659843 uncertain significance RYR1-Related Disorders 2018-03-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 4757 of the RYR1 protein (p.Arg4757His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs768360593, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RYR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
PreventionGenetics,PreventionGenetics RCV000721359 SCV000852400 uncertain significance not provided 2013-10-30 criteria provided, single submitter clinical testing

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