ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14518A>T (p.Met4840Leu)

dbSNP: rs933599635
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000721377 SCV000621663 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing The M4840L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M4840L variant is not observed in large population cohorts (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
PreventionGenetics, part of Exact Sciences RCV000721377 SCV000852422 uncertain significance not provided 2013-10-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001853690 SCV002221911 uncertain significance RYR1-related disorder 2022-10-04 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4840 of the RYR1 protein (p.Met4840Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452823). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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