ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13477C>G (p.Pro4493Ala) (rs149455643)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623122 SCV000741877 uncertain significance Inborn genetic diseases 2016-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Fulgent Genetics,Fulgent Genetics RCV000764199 SCV000895202 uncertain significance Myopathy, Central Core; Malignant hyperthermia, susceptibility to, 1; Minicore myopathy; Congenital myopathy with fiber type disproportion 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000551114 SCV000659818 uncertain significance RYR1-Related Disorders 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 4493 of the RYR1 protein (p.Pro4493Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs149455643, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with adult onset myalgia as well as in an unaffected control individual (PMID: 21674524). ClinVar contains an entry for this variant (Variation ID: 478185). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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