ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13910C>T (p.Thr4637Ile) (rs118192134)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536286 SCV000659834 uncertain significance RYR1-Related Disorders 2017-03-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 4637 of the RYR1 protein (p.Thr4637Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with central core disease (PMID: 12565913). ClinVar contains an entry for this variant (Variation ID: 65995). 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: "Unknown"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Thr4637Ala) has been determined to be pathogenic (PMID: 11113224). This suggests that the threonine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic. In addition, this sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). In summary, this variant is a rare missense change that has been reported in an affected individual and occurs in a functionally important region of the RYR1 protein. However, the available evidence is currently insufficient to conclusively determine this variant's role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneReviews RCV000056242 SCV000087331 pathologic Myopathy, Central Core 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119488 SCV000154395 not provided not provided no assertion provided not provided

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