ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.12210T>G (p.Ile4070Met)

gnomAD frequency: 0.00004  dbSNP: rs765758001
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721264 SCV000852285 uncertain significance not provided 2013-10-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000812450 SCV000952763 uncertain significance RYR1-related disorder 2023-10-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4070 of the RYR1 protein (p.Ile4070Met). This variant is present in population databases (rs765758001, gnomAD 0.004%). 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: 590397). 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.
GeneDx RCV000721264 SCV001988285 uncertain significance not provided 2019-01-16 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics RCV002477664 SCV002792755 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2021-10-12 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000721264 SCV003813152 uncertain significance not provided 2021-09-02 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999816 SCV004816032 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 4070 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 6/282864 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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