ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.10729C>T (p.Arg3577Trp) (rs538497899)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520577 SCV000619480 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The R3577W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R3577W variant is observed in 11/8611 (0.1%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R3577W 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. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000707061 SCV000836141 uncertain significance RYR1-Related Disorders 2018-01-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 3577 of the RYR1 protein (p.Arg3577Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs538497899, ExAC 0.1%). 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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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