ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.10648C>T (p.Arg3550Trp) (rs536304635)

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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 RCV000656969 SCV000332275 uncertain significance not provided 2015-06-22 criteria provided, single submitter clinical testing
GeneDx RCV000656969 SCV000565506 uncertain significance not provided 2018-12-14 criteria provided, single submitter clinical testing The R3550W variant has been previously reported as a variant of uncertain significance in an individual with myopathy, who also harbored a second RYR1 frameshift pathogenic variant; his affected son was found to only harbor the frameshift variant, thus indicating that R3550W did not segregate with the phenotype in the family (Laughlin et al., 2017).The R3550W variant was observed in 56/30782 alleles (0.2%) alleles from individuals of South Asian background (Lek et al., 2016). The R3550W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000338681 SCV000412748 likely benign Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000398390 SCV000412749 likely benign Myopathy, Central Core 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000280179 SCV000412750 likely benign Multiminicore Disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000335257 SCV000412751 likely benign Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000818112 SCV000958709 uncertain significance RYR1-Related Disorders 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 3550 of the RYR1 protein (p.Arg3550Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs536304635, ExAC 0.2%). This variant has been observed in an individual affected with centronuclear myopathy, however in that family a separate RYR1 variant was present in both affected individuals (PMID: 29178655). ClinVar contains an entry for this variant (Variation ID: 281479). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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 RCV000656969 SCV000852220 uncertain significance not provided 2016-05-31 criteria provided, single submitter clinical testing

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