ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13672C>T (p.Arg4558Trp) (rs771741606)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552685 SCV000659824 uncertain significance RYR1-Related Disorders 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 4558 of the RYR1 protein (p.Arg4558Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs771741606, ExAC 0.001%). This variant has been reported in a family affected with centronuclear myopathy (PMID: 28818389). ClinVar contains an entry for this variant (Variation ID: 478187). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg4558 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 17226826, 18253926, 25747005), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000754735 SCV000882623 likely pathogenic Myopathy, Central Core 2018-10-08 criteria provided, single submitter clinical testing

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