ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.9635A>G (p.Glu3212Gly) (rs199738299)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512826 SCV000608901 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000512826 SCV000534154 uncertain significance not provided 2018-07-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The E3212G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E3212G variant is observed in 45/82,358 (0.5%) alleles from individuals of European background the ExAC dataset and has been observed as apparently homozygous in an individual undergoing testing at GeneDx (Lek et al., 2016). This 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 analyses, including protein predictors and evolutionary conservation, support 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 RCV000285479 SCV000412664 likely benign Multiminicore Disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000342818 SCV000412665 likely benign Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000391499 SCV000412666 likely benign Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000288960 SCV000412667 likely benign Myopathy, Central Core 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000556213 SCV000660096 uncertain significance RYR1-Related Disorders 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 3212 of the RYR1 protein (p.Glu3212Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs199738299, ExAC 0.09%). This variant has not been reported in the literature in individuals with a RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 329090). 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: "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.

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