ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14645C>T (rs193922884)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000119538 SCV000576796 pathogenic not provided 2017-04-19 criteria provided, single submitter clinical testing The T4882M pathogenic variant in the RYR1 gene has been previously reported in individuals with congenital myopathy who harbored an additional variant on the opposite RYR1 allele (Todd et al., 2015). The T4882M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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 conserved across species, and missense variants in nearby residues (M4880T; M4881I; F4886L; H4887Y) have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000695746 SCV000824263 pathogenic RYR1-Related Disorders 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 4882 of the RYR1 protein (p.Thr4882Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs193922884, ExAC 0.01%). This variant has been observed in combination with or on the opposite chromosome (in trans) from other pathogenic variants in several individuals affected with neuromuscular diseases (PMID: 26578207, 27854218), and to segregate with disease in affected families (PMID: 26578207). This variant has also been observed in the heterozygous state in a family affected with childhood onset myopathy (PMID: 18312400). ClinVar contains an entry for this variant (Variation ID: 133083). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. For these reasons, this variant has been classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119538 SCV000154445 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119538 SCV000852438 uncertain significance not provided 2015-09-18 criteria provided, single submitter clinical testing

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