ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.4405C>T (p.Arg1469Trp) (rs200546266)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148819 SCV000190558 uncertain significance Congenital myopathy 2014-06-01 no assertion criteria provided research
GeneDx RCV000520385 SCV000617748 likely pathogenic not provided 2017-10-25 criteria provided, single submitter clinical testing The R1469W variant in the RYR1 gene has been reported previously in association with centronuclear myopathy, in two affected siblings who were heterozygous for the R1469W variant and another variant (Wilmshurst et al., 2010). The R1469W variant has also been reported in individuals with malignant hyperthermia who were also heterozygous for the R1469W variant and another variant (Gillies et al., 2015; Fiszer et al., 2015). The R1469W variant is observed in 16/66172 (0.024%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The R1469W 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. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1469W as a likely pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000501380 SCV000596898 uncertain significance not specified 2016-12-07 criteria provided, single submitter clinical testing
Invitae RCV000534955 SCV000659940 uncertain significance RYR1-Related Disorders 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1469 of the RYR1 protein (p.Arg1469Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs200546266, ExAC 0.02%). This variant has been reported in the literature in several individuals affected with centronuclear myopathy (PMID: 20839240, 21911697) and in several individuals affected with malignant hyperthermia (PMID: 25735680, 25658027). ClinVar contains an entry for this variant (Variation ID: 161372). 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: "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 RCV000520385 SCV000852620 likely pathogenic not provided 2017-05-12 criteria provided, single submitter clinical testing

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