ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.12881C>T (p.Thr4294Met) (rs587784372)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000147411 SCV000340017 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing
GeneDx RCV000346113 SCV000617752 uncertain significance not specified 2017-06-02 criteria provided, single submitter clinical testing The T4294M variant in the RYR1 gene has been reported previously in one African American individual who experienced a single episode of exertional rhabdomyolysis with myoglubinuria, and showed a positive contracture response to both caffeine and halothane (Sambuughin et al., 2009). This individual also harbored three other RYR1 variants (phase unknown) and T4294M was noted to be absent in 230 control subjects of varying ethnicity (Sambuughin et al., 2009). Adequate data is not available in large population cohorts to assess the frequency of this variant in publicly available databases; however, the T4294M variant is observed in 28/69900 (0.04%) alleles from presumably healthy individuals tested at GeneDx. The T4294M 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 not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret T4294M as a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000147411 SCV000194799 uncertain significance not provided 2014-01-23 criteria provided, single submitter clinical testing
Invitae RCV000553067 SCV000659801 uncertain significance RYR1-Related Disorders 2017-12-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 4294 of the RYR1 protein (p.Thr4294Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. While this variant is not present in population databases (rs587784372), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, along with a 9 bp duplication (c.12861_12869dup (p.T4288_A4290dup)), has been reported in an individual affected with exertional rhabdomyolysis and malignant hyperthermia susceptibility. It is inconclusive which, if either of the two variants, is pathogenic in this individual (PMID: 19807743). ClinVar contains an entry for this variant (Variation ID: 159834). 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). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. While the frequency information is unreliable from the population databases and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics RCV000147411 SCV000852323 uncertain significance not provided 2016-02-15 criteria provided, single submitter clinical testing

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