ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.8330A>T (p.Tyr2777Phe) (rs769276412)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520784 SCV000621209 uncertain significance not provided 2017-09-28 criteria provided, single submitter clinical testing The Y2777F variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y2777F variant is observed in 4/126,018 (0.0032%) alleles from individuals of European (non-Finnish) background in the gnomAD dataset (Lek et al., 2016). The Y2777F 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 Y2777F as a variant of uncertain significance.
Invitae RCV000696145 SCV000824693 uncertain significance RYR1-Related Disorders 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with phenylalanine at codon 2777 of the RYR1 protein (p.Tyr2777Phe). The tyrosine residue is highly conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is present in population databases (rs769276412, ExAC 0.002%). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 452402). 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 phenylalanine 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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