ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.5000G>A (p.Arg1667His) (rs138978909)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626708 SCV000747411 uncertain significance Elevated serum creatine phosphokinase; Myalgia; Exercise-induced myalgia 2017-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000414466 SCV000492295 uncertain significance not specified 2016-12-13 criteria provided, single submitter clinical testing The R1667H variant in the RYR1 gene has not been reported previously as a germline pathogenic variant, nor as a benign variant, to our knowledge. The R1667H variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1667H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1667H as a variant of uncertain significance.
Invitae RCV000543824 SCV000659952 uncertain significance RYR1-Related Disorders 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1667 of the RYR1 protein (p.Arg1667His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs138978909, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 28259615). ClinVar contains an entry for this variant (Variation ID: 373680). 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: "Tolerated"; PolyPhen-2: "Possibly 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 RCV000721573 SCV000852664 uncertain significance not provided 2013-10-22 criteria provided, single submitter clinical testing

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