ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.12880A>G (p.Thr4294Ala) (rs1003914966)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000605948 SCV000731044 likely benign not specified 2017-09-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000540726 SCV000659800 uncertain significance RYR1-Related Disorders 2017-10-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 4294 of the RYR1 protein (p.Thr4294Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. While this variant is not present in population databases (no RSID), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a RYR1-related disease. A different missense substitution at this codon (p.Thr4294Met) has been reported in a single individual affected with exertional rhabdomyolysis (PMID: 19807743). The clinical significance of this variant is not known. 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. This sequence change is located in the C-terminal mutational hotspot 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 is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics RCV000721297 SCV000852322 uncertain significance not provided 2015-11-09 criteria provided, single submitter clinical testing

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