ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14915C>T (p.Thr4972Ile) (rs199866740)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000209974 SCV000265752 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
Invitae RCV000541881 SCV000659863 uncertain significance RYR1-Related Disorders 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 4972 of the RYR1 protein (p.Thr4972Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs199866740, ExAC 0.03%). This variant has been reported in an individual affected with limb-girdle muscular dystrophy (PMID: 25214167) ClinVar contains an entry for this variant (Variation ID: 224407). 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: "Benign"; Align-GVGD: "Class C0"). This missense change is located in the C-terminal region the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090, 23919265). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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